We found that new infections among women at older ages are typically benign, with low absolute risks of persistence, CIN 2+ and especially CIN 3+. The absolute risk and etiologic fraction of subsequent cancer, therefore, can be expected to be extremely low. We confirmed that the frequency of new infections, which are the only ones that the current vaccines can prevent (34
), decreases with age. Therefore, screening will initially detect old and new infections but sequential rounds will increasingly detect new infections. The formulation of cervical cancer prevention policy among adult women should take into consideration the particular natural history of HPV and cervical neoplasia at those ages.
Longitudinal data for all HPV infections detected during 7 years within the Guanacaste population-based cohort allowed us to directly compare the risk of persistence and progression to CIN 2+ for carcinogenic HPV infections detected prevalently at enrollment (after being persistent for perhaps many years) vs those detected during follow-up (newly detected) in women of several age groups. We confirmed previous findings (16
) that, for prevalently detected infections, the risk of persistence increases with the increasing age of the woman. In women with prevalent infections, subsequent risk of CIN 3+ also increased with age, although the trend in this analysis was not statistically significant for the less robust CIN 2+ endpoint (36
). However, newly detected infections, including HPV-16 infections, were able to be cleared as quickly by older women as by younger women, and for newly detected infections, the older women had a similar or slightly decreased risk of CIN 2+ and especially CIN 3 compared with younger women.
This direct age-specific comparison of prevalent and newly detected infections resolved previous reports that had seemed discrepant. Cross-sectional studies in which prevalently detected infections were revisited some years later showed an increasing risk for persistence of infection and/or risk of CIN 2+ with increasing age of the woman (16
). However, analysis of duration of HPV infections detected as “incident” or new during follow-up among women in two other cohorts (18
) showed that these infections were of similar duration irrespective of the age of the woman, and one-third cohort (38
) reported shorter duration among women at older ages. Our data reconcile these findings: The apparent contradiction is resolved by the recognition that, among older women, prevalently and newly detected infections are found at different stages of HPV natural history, with very different implications for prevention programs based on HPV vaccination or HPV testing.
The differences can be understood in the context of the typical “life cycle” of HPV infections, which starts at transmission. The peak transmission of HPV infections usually occurs early in the first years following initiation of sexual intercourse because HPV infections are so endemic and easily transmitted (7
). The average age of first sexual intercourse tends to center homogeneously on a few years in adolescence and young adulthood. As a corollary, most infections among young women are recently acquired, regardless of whether they are detected prevalently in a cross-sectional screen or in the next few months or years as new. It is not surprising, therefore, that we found no distinction between prevalent and newly detected infections at younger ages in terms of persistence or risk of CIN 2+ in the subsequent 3 years.
As the HPV infection persists, the situation grows more complex. Most infections clear quickly within 6–12 months of detection, but the longer that a carcinogenic HPV infection lasts in a detectable state, the higher the risk that it will continue to persist, or not clear under immunologic control, or lead to a CIN 3+ (31
). By the time that such an infection has persisted for approximately 2 or more years, an associated risk of CIN 2 (a part of which is incipient CIN 3) and even CIN 3 is easily noted (11
). Initially, miniscule CIN 3 lesions can take years to grow to a size that is able to be visualized by colposcopy, biopsied, and diagnosed microscopically (35
The hazard of CIN 3 rises and falls again as a secondary peak that echoes the earlier peak in HPV infection among younger women. The average time from a carcinogenic HPV infection to clinical diagnosis of CIN 3 (n.b., we are discussing time of diagnosis, not the underlying natural history) is shortened by intensive screening and aggressive management; thus, the CIN 3 that we found associated with prevalent HPV infections tended on average to occur among women almost a decade older than the many fewer cases we found following newly detected infections.
In turn, the incidence of invasive cancers rises as a tertiary wave. Comparison of the average age of cancer diagnosis and the average age of first sexual intercourse within a given population suggests that the typical time interval for a carcinogenic HPV infection to cause CIN 3 and then invasive cervical cancer is greater than 20–25 years. Thus, we observed almost all cancers in the Guanacaste cohort among women who had prevalent long duration infections. There was a very low but nonnull risk of cervical cancer among women who initially tested as HPV negative (40
). Notably, these exceptional cases of rapid cancer progression are very important and must be weighed against population averages when screening policy is discussed.
We believe that prevalently detected infections among older women (≥42 years of age in this cohort) include two groups of long-term infections likely to persist longer than new infections: those infections that have an associated CIN 2+ lesion and a residual small fraction of HPV infections that seem to persist for years without evidence of CIN 2+. Although some prevalently detected infections might have been transmitted within the previous few years or might have recently reappeared from an ill-defined latency, most prevalent detection at older ages corresponds to continually detectable infections of long duration, thereby predicting an elevated risk of further persistence and eventual CIN 2+. Although they were less common, some examples of benign persistence were observed: 25 (2.2%) of the 1128 carcinogenic HPV infections had HPV DNA that was detectable for 7 years, with no evidence of cervical pathology despite repeated multimodal examinations. We also note that there was no evidence that the differences in HPV persistence that we observed among different age groups could be explained by confounding by behavioral covariates, such as parity or oral contraceptive use (data not shown).
Carcinogenic HPV infections that were newly detected upon screening among older women likely represent a heterogeneous set in terms of the real duration or “age” of the infection. Even though it is not possible to distinguish true incidence from temporary loss of immune control of infections initially transmitted years before, the main analysis showed a similar behavior of newly detected infections irrespective of the age of detection, specifically, that there is low risk of subsequent overt HPV persistence and risk of CIN 2+.
As a final point regarding HPV natural history, we confirmed that the infections found only by PCR and not by HCT, that is, the infections with the very lowest viral loads tended to lead to a very low risk of CIN 2+, even though they persisted on average as long as infections with higher viral loads. Most CIN 2+ was caused by HPV-16, and an association between low viral load and low risk of subsequent CIN 2+ is well described for this HPV type but not for others (25
The main limitation of this study is the short follow-up time of incident infections. Although this large cohort study evaluated all carcinogenic HPV infections in a true population sample of women aged 18 years and older, the most important conclusion that newly detected HPV infections are benign at any age might not hold beyond the 7 years of follow-up we achieved. We are currently planning a final screening of the cohort at approximately 20 years past enrollment.
Understanding the relevance of the concept of duration of infection can improve cervical cancer prevention strategies that integrate prophylactic vaccination with HPV screening. For example, evidence that newly detected infections in older women do not harbor a higher risk of HPV persistence or CIN 2+ than in younger women and that older women acquire fewer new infections indicates that the possible benefit of vaccinating older women is much reduced, as measured by potential number of averted CIN 2, CIN 3, and cervical cancer diagnoses per 1000 women vaccinated. It is important to add that the sharp peak in prevalent CIN 2+ caused by HPV-16 or HPV-18 that was seen among women around age 30 years upon their enrollment in the Guanacaste cohort likely would have occurred years earlier if these women would have been adequately screened before entering the cohort; thus, vaccination of women in their late 20s or even in their early 20s would not have prevented the majority of these cases.
Screening with HPV must also consider the duration of infections. First-time screening of a population using HPV testing will detect prevalent infections associated with high risk of persistence, CIN 2, and CIN 3, providing excellent risk stratification because HPV negativity predicts very low risk of subsequent cervical cancer. However, subsequent screening will detect newly apparent infections, which even at older ages have a lower positive predictive value, arguing against the use of HPV screening at too-frequent intervals. A one-time HPV DNA assay cannot determine duration of an infection. Our results motivate a search for biomarkers that correlate with duration of HPV infection and might improve prediction of risk.
In conclusion, more than 90% of new infections with carcinogenic HPV types are benign, whereas long duration of infection predicts risk of further persistence, risk of associated CIN 3, and eventual cervical cancer. Vaccination and screening programs must specify clearly what kind of infections they are targeting to avoid mistaken conclusions.