By enrolling a cohort of newly sexually active young women with minimal previous exposure to HPV, we were able to observe the early natural history of truly incident HPV infections in the female genital tract. Consistent with previous longitudinal studies (of both prevalent and incident infections) (8
), we observed that 90% of incident type-specific infections in our cohort became undetectable within two years (with half of all infections becoming undetectable within 9.4 months). Re-detection after a period of negativity was not uncommon. Nineteen percent of type-specific infections that became undetectable were re-detected within one year, and sequencing data indicated the presence of the same type-specific variant in samples collected before and after the intercurrent negative period. Re-detection of the same HPV type after intercurrent negative periods may reflect fluctuations in viral levels (or low-level viral shedding (2
)), sampling inconsistencies, intercurrent false-negative test results, or new infection. Regardless, estimates of duration or clearance that are based on one or two negative HPV tests following a string of positive tests may be insufficient for distinguishing between persistent and transient infections. Furthermore, while our data do not address whether repeat detection in the early course of an HPV infection is predictive of long-term viral persistence, we previously reported that it was not uncommon for long-term persistent infections (defined as infections detected four to twelve years after incident detection) to have been detected sporadically in the first several years following incident detection (2
Characterizing the early course of new HPV infections may further our understanding of infectivity and provide estimates that can be used in models of HPV transmission. Presumably, there is a positive correlation between duration of detectable HPV DNA and duration of infectivity, suggesting that repeat DNA detection is associated with a longer window of infectivity and therefore a greater probability of transmission to new sex partners (based on the positive relationship between the duration of infectivity and the reproductive rate of an infection (3
)). Therefore, in order to identify factors that might increase an infected woman’s risk of transmitting her infection to a new sex partner, we sought to identify risk factors for repeat versus transient detection (in the first eight months after incident infection).
Smoking was positively associated with repeat HPV detection, but the proportion of smokers in our cohort was small and the association did not reach statistical significance. Although smoking is a clear risk factor for cervical cancer (6
), the relationship between smoking and HPV persistence in the literature is inconsistent and the stage at which smoking exerts an effect on carcinogenic progression is unclear (8
Though not statistically-significant, report of new sex partners in the 8 months prior to incident detection was associated with an increased likelihood of repeat detection compared to report of only non-new sex partners (2.5-fold increase) or no sex partners (5-fold increase). We previously showed that report of more than one new partner in the eight months prior to incident HPV-16 or HPV-18 infection was associated with increased E7 mRNA viral levels (9
) (and higher viral levels have been linked with persistent detection (10
)). No statistically significant sexual behavioral determinants of persistent versus transient infections were identified.
We also evaluated viral determinants of repeat detection, and found that site of initial infection was a strong predictor of repeat detection. Compared to infections that were first detected in the cervix only, those that were detected in the vulva/vagina only were twelve times as likely to be repeatedly detected and those that were detected in both the cervix and the vulva/vagina were seventeen times as likely to be repeatedly detected. Alpha-genus HPV infection that involves the entire genital tract (versus one site only) may be associated with higher viral loads. It is also possible that our results may partially reflect the potential for vulvar/vaginal infections to precede cervical infections, as incident infections following this trajectory would be detected at at least two consecutive visits (first in the vulva/vagina and subsequently in the cervix) (13
While it is well-established that persistent high-risk HPV infection is a necessary step in cervical carcinogenesis (1
) (with a one-year minimum proposed as a clinically-relevant threshold for identifying persistent high-risk infections that are likely to progress to precancer (CIN 3+) (18
)), the role of early repeated detection of the same high-risk HPV type on the infection-to-precancer continuum is unclear. Our results do suggest, however, that in the early stages of infection, development of clinically-evident cervical lesions has little to do with persistent detection of HPV. Consistent with our findings in a previous cohort (19
), we found that low-grade cervical SILs were a common manifestation in the year following incident HPV infection. In those who developed SIL in that time frame, the median induction time was less than six months (shorter than the median duration of continuously detectable infections in this cohort). Most of these early, low-grade SILs regress spontaneously and are unrelated to cervical precancer (19
One limitation of our study is that we did not dissect cervical tissue, and therefore could not accurately attribute lesions to specific HPV types. Co-infection with multiple HPV types was common, as was sequential infection with new HPV types. Furthermore, sixty percent of cervical SILs were positive for multiple HPV types in concurrently-collected cervical swab samples, a finding that is consistent with data from an Oklahoma colposcopy clinic showing that 75% of women with ASCUS or low-grade SIL tested positive for multiple HPV types in the cervix (in that study, younger age was also associated with multiple type infections in all cervical disease categories) (20
). Therefore, our estimates of the median time from first incident HPV detection (with any type) to cervical SIL among women who developed SILs within 12 months of first incident HPV infection were likely overestimates, as the HPV type(s) present in the cervical swab at the time of SIL detection were not necessarily the same type(s) present at the time of first incident HPV detection. While we could not estimate the unconstrained median time to SIL development (due to limited follow-up), restricting our estimate to women who developed SILs within 12 months of their first incident HPV infection was a reasonable analytical approach, as all cervical HPV types detected concurrently with new SILs were first detected within the prior 12 months (data not shown). SILs detected more than 12 months after first incident HPV infection were likely due to more recently acquired HPV types. Another limitation is the potential for false-positive or false-negative results in either our HPV or cytologic testing. (The three cases of SIL that were detected prior to first incident HPV infection likely indicate either false-positive Pap results or false-negative HPV results.)
In summary, our results indicate that sporadic detection of incident HPV infections is common in newly sexually active young women. Whether or not potentially modifiable risk factors can be identified to reduce the duration of infectivity (and the likelihood of transmission to new sex partners) remains unclear. Finally, clinically-evident low-grade cervical lesions were a common early manifestation of HPV infections, but did not appear to be associated with early HPV persistence.