In this long-term (16-year) prospective study, we confirmed the critical role of persistent carcinogenic HPV infections in predicting risk of subsequent cervical neoplasia in women aged 30 years and older.
The incidence of ICC or CIS following baseline infection by the 12 carcinogenic HPV types was 0.37% per person-year, which was more than 20 times the risk in HPV-negative women. We observed a sustained low risk of ICC or CIS in absence of any carcinogenic HPV type at baseline. In fact, no ICC and only one CIS developed among HPV-negative women who were aged 55 years and older. The extraordinary risk stratification of cervical cancer provided by HPV testing in this cohort supports the usefulness of HPV testing, at long intervals, for cervical cancer screening.
Persistence of carcinogenic HPV infections was critical to the magnitude of ICC or CIS risk. Type-specific HPV persistence for a duration of 2 years elevated cervical cancer risk substantially for all individual carcinogenic HPV types: Risks were elevated two- to tenfold compared with single time-point detection. HPV infections that are detected only at a single time-point tend to clear rapidly; clearance gradually reaches a plateau around 3–5 years of follow-up (25
). Two-year persistence (40.9%) in our study served as a biomarker of chronic or long-term infection, which was linked to increased risk of subsequent cancer development. As the duration of infection increased, risk increased; thus, the risk of ICC or CIS following persistence increased with age, in line with the known natural history of HPV infections that are usually acquired sexually at young ages. Our findings suggest that, if upon testing an HPV infection is found, retesting 2 years later would provide useful guidance as to the duration of infection and its risk. Although the theoretical importance of persistence cannot be overemphasized, many women and their clinicians are reluctant to wait for clearance because the first positive result (especially at older ages) does indicate increased risk compared with a negative result. Clinical guidelines will need to achieve a balance of clinical attention and restraint.
When baseline HPV infections cleared rather than persisted, subsequent cervical cancer risk was extremely low. This finding demonstrated that overt persistence rather than one-time infection is associated with a high risk of cancer. In fact, we observed low cervical cancer risk following HPV acquisition at any age, confirming that age does not modify the cancer risk following incident infections (17
). Because it is the duration of overtly detectable infection that most strongly predicts cancer risk, it would not be useful to repeat HPV testing on a frequent basis. Any new infections that might be found would be low-risk, and could not be interpreted like prevalent (possibly persistent) infections found on the first screen. The proper interval for repetition of HPV screening is not yet known, but it may exceed 5 years (26
Our findings extend the conclusions of recent randomized clinical trials that showed a high sensitivity of HPV testing to predict the risk of CIS over shorter intervals of a few years (6
). However, in our study, HPV testing at a single time point did not perfectly predict outcome during the entire follow-up period. Only 13% of participants were HPV positive at baseline, and they comprised 70% of all of the women who developed ICC or CIS. In other words, 30% of the cancers were diagnosed in the remaining 87% of participants who were HPV negative initially. These cancers were presumably caused by new infections that were acquired after entry into the study. New infections acquired after 30 years of age confer low risk (ie, in terms of the fraction of cancers, including CIS, that they cause compared with infections acquired earlier in life) but they are not without risk. It is quite possible that some cases of CIS and even ICC were caused by carcinogenic HPV infections that were acquired after the baseline and/or after the second examination 2 years later. However, the fraction of ICC diagnoses without HPV detection did not increase with time since the last screening (data not shown). In other words, a fraction of the women with ICC who were diagnosed throughout follow-up were HPV negative when we initially measured them, for unknown reasons. As the only tentative clue, women with cancers who were not preceded by HPV detection tended to be younger than those in whom we did find HPV infections. It is important to point out that during 16 years follow-up, only nine out of 8780 women who were baseline HPV negative developed ICC, and only three out of 5396 women who tested negative at both the baseline and second examinations developed ICC. These estimates might be useful to guide publicly funded prevention efforts, which will need to consider how often to rescreen women who initially tested HPV negative.
The importance of HPV16, HPV58, HPV52, HPV18, HPV31, and HPV33 in this study was consistent with our previous cross-sectional study reporting the association between prevalent cervical cancer and HPV infection at baseline (3
), and the distribution of HPV types in cervical cancers diagnosed in Asia (27
). Moreover, our findings complement a recent long-term follow-up among young women aged 20–29 years in Denmark that observed similar risk stratification related to HPV persistence vs HPV negativity (20
) and are consistent with other cohort data (30
Compared with detection of all carcinogenic HPV types as a pool, genotyping may provide further information to improve the specificity of HPV testing. Even among the carcinogenic types, HPV16 and HPV58 were found to cause a higher risk of ICC or CIS than other carcinogenic HPV types. Full typing of HPVs may be useful to optimize the sensitivity and specificity of HPV test for detecting cervical cancers; alternatively, partial typing might provide as much risk stratification as clinicians need.
The major limitation of our study was the lack of HPV typing at the time of cervical cancer diagnoses. We might have misclassified the causal HPV types in some cases due to the transient nature of HPV infections. Moreover, our use of registry linkage rather than active follow-up probably led to under-ascertainment of cervical cancers, particularly for CIS. In this context, we did note a higher proportion of ICC among all of the cervical cancers in this prospective series (34/68 = 50.0%) than in the data from baseline (20/56 = 35.7%). Along the same lines, we noticed an apparent difference between the cumulative risk of ICC or CIS in our study and cumulative risk of CIN3, which includes CIS, in Western countries (20
). In Western countries, the cumulative incidence of CIN3 is relatively high, and it is much more frequent than ICC. In comparison, in Taiwan, we saw less CIS, even at baseline. The difference in CIN3 diagnosis might be due in part to CIS being a slightly more stringent and serious diagnosis, or to less-intensive screening in Taiwan. Also, many women with the precursors to CIN3 may have experienced regression of their disease over time before they entered the age range of the cohort.
In conclusion, this cohort study extends to 16 years the usefulness of HPV testing for cervical cancer screening. In women older than 30 years who test HPV positive, it is helpful to perform a repeated HPV test 2 years later to improve the predictive value and specificity of cervical cancer screening. The accumulated evidence suggests that it is time to include HPV testing in cancer screening programs for the general population. HPV negative women will obtain superior reassurance of reduced risk. The challenge that remains is to devise optimal management guidelines for HPV-positive women, which may include a careful wait-and-see approach to monitor viral persistence vs clearance.