In the Netherlands, human papillomavirus (HPV) infection is common among women with normal cytology.1 The prevalence of HPV is reported to be highest in sexually active young women and decreases with age.2, 3
Persistent infection with ≥1 high-risk types of human papillomavirus (HR-HPV) is reported to be the unifying risk factor for the development of cervical intraepithelial neoplasia (CIN).4, 5
The prevalence of both HPV infection and cervical cancer are closely related to age, but the age profiles differ. In the Netherlands, the peak prevalence of HPV infection precedes the peak prevalence of high-grade CIN and cervical cancer.6
A positive HPV test can be followed by a negative one, and vice versa. Such alternating infections are frequently encountered in our screening practice. The transient HPV infections are frequently studied but, to the best of our knowledge, there are no studies published to date that include a large number of sexually active women of all ages to obtain insight into the consequences of alternating HR-HPV infection in women with negative cytology.
Most HPV studies rely on the analysis of referral populations (ie, on women with cytologic abnormalities).2, 4, 5 For the purposes of healthcare planning decisions, studies using nonreferral data and cytology-negative smears would appear to be preferable. Therefore, we decided to readdress an existing database with HR-HPV and the histology results of patients participating in primary screening for cervical cancer, thereby allowing us to obtain insight in the consequences of alternating HR-HPV infection on progression to CIN.
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- MATERIALS AND METHODS
The results of the current study, based on the analysis of 703 women with multiple tests who were extracted from the dataset of 21,480 cytologically negative smears with HPV tests, suggest that alternating HR-HPV infection is common among all women throughout the Netherlands. In the literature, the term “alternating HPV infection” is not used. We propose to add this term to the medical vocabulary because this phenomenon might be significant in our understanding of cervical carcinogenesis. The transience of HR-HPV infection is well known from the literature and describes the loss of HPV infection. This phenomenon occurs more frequently in younger women,4, 10 and appears to decline with age. In addition, the acquisition of HPV was found to predominate at a younger age.11 We found a nevertheless remarkably high prevalence of 17% for alternating HR-HPV infection in women age older than 40 years (Table 1). The probability of finding a woman in the HR-HPV–positive group must be even smaller than that found in the current study, because some women could have cleared a HR-HPV infection between 2 positive tests.12, 13 This would have to had gone undetected because of our coarse sampling regime. These women should have been included in the group of patients with alternating HR-HPV infection. Therefore, it appears likely that alternating HR-HPV infection is even more common than was found in the current study.
The declining age effect for persistent and alternating HR-HPV infection in Table 1 can be attributed to various independent causes (eg, fewer sexual partners and an acquired HPV immunity).14 Another possible explanation is the latent presence of the HPV virus during the majority of the woman's life, at levels below the detection threshold of the HPV tests.15, 16 This infection is reactivated at irregular instances (ie, a recurrent self-infection). Another explanation for monogamous couples is an oscillation of infection and clearing between sexual partners.17, 18 In instances in which this was the case, the infection was always present in either 1 or both of the partners, and was never cleared completely.
During the follow-up period in the current study, 6 of the 703 women (0.9%) developed CIN. These 6 women had at least 1 positive HR-HPV test. Other studies have indicated that the continuous presence of HR-HPV is necessary for the development, maintenance, and progression of CIN lesions.4, 19–23 In 3 studies performed in women with negative cytology, a substantial proportion of the women had developed either type 2 or type 3 CIN at the time of last follow-up.19, 23, 24 In the study by Rozendaal et al.,23 0.4% of the women with negative cytology developed type 3 CIN, and 6 had a HR-HPV–positive test whereas only 1 woman had a HR-HPV–negative test. In the study by Bulkmans et al.,24 0.6% of the women developed type 3 CIN; 12 of these women had type 3 CIN with a positive HR-HPV test and 1 woman had a negative HR-HPV test. These percentages appear to be in agreement with the findings of the current study. In the study by Koutsky et al.,19 the incidence of CIN was found to be 12%. We suspect that the higher incidence is because of a selection bias in the studied population; the women had presented themselves for the evaluation of sexually transmitted diseases. Unfortunately, in both studies by Rozendaal et al.,23, 24 the authors were unable to examine alternating HR-HPV infection because patients were tested only once for HPV. This also might be the reason why in both studies, a woman developed type 3 CIN without a positive HR-HPV test. By testing women more often, these women might be identified. In the Netherlands, a large study had focused on the question of the possible consequences of a positive HR-HPV test for progression to CIN in Dutch women. This study might provide more insight into the efficiency of the use of a HR-HPV test in the national screening program.25
The results of the current study demonstrate that a HR-HPV test can alternate from positive to negative and vice versa. In the HART study (a multicenter screening study of 11,085 British women) by Cuzick et al.,16 there were 189 women with normal or atypical cells of undetermined significance (AS-CUS) cytology who were selected for a second HPV test within 12 months. Of these women, 80 had 2 HR-HPV–negative tests, 117 women had 2 HR-HPV–positive tests, and the remaining 92 women had a positive test followed by a negative one and therefore were considered to have alternating HR-HPV infection.16
Clinical and experimental evidence suggest that, similar to other mechanisms of carcinogenesis, HPV infection alone is not sufficient to result in cervical cancer but requires other factors that may influence local immune responses and/or result in other genetic alterations.26, 27 In an overview study, Cuzick et al. supported the use of HPV testing as the primary screening test, with cytology reserved for women whose test was positive for HPV.28
As is clear from the current study, the frequency of HR-HPV infection is high even for women age older than 40 years. Therefore, we believe that it might be wise to include women age 40 years and older who have negative cytology for HPV testing. The results of the current study also demonstrate that of those women who were tested at least twice and found to be HR-HPV negative, none had developed CIN at the time of last follow-up. For these women with a low risk of developing cervical cancer, the interval between testing might be prolonged.