No abstract

No abstract

Participants 28 073 women who had not responded to two invitations to the regular cervical screening programme: 27 792 women were assigned to the self sampling group and invited to submit a self collected cervicovaginal sample for HPV testing; 281 were assigned to the recall control group and received a second reinvitation for conventional cytology. Intervention Women with a positive result on the high risk HPV test on their self sample material were referred to their general practitioner. Women with abnormal results on cytology were referred for colposcopy. Women with normal results on cytology were re-evaluated after one year by cytology and high risk HPV testing and referred for colposcopy if either result was positive. Main outcome measures Attendance rate in both groups and yield of cervical intraepithelial neoplasia grade II/III or worse (≥CIN II/≥CIN III) in self sampling responders. Results The compliance rate in the self sampling group was significantly higher than in the control group (crude 26.6% v 16.4%, P<0.001; adjusted 27.5% v 16.6%, P<0.001). The number of detected ≥CIN II and ≥CIN III lesions in self sampling responders was 99 (1.3%) and 76 (1.0%), respectively. Self sampling responders who had not participated in the previous round of screening (43%) had increased relative risks of ≥CIN II (2.04, 95% confidence interval 1.27 to 3.28) and ≥CIN III (2.28, 1.31 to 3.96) compared with self sampling women who had been screened in the previous round (57%). ConclusionsOffering self sampling by sending a device for collecting cervicovaginal specimens for high risk HPV testing to women who did not attend regular screening is a feasible and effective method of increasing coverage in a screening programme. The response rate and the yield of high grade lesions support implementation of this method for such women. Trial registration ISRCTN45527158.

Cytological cervical screening is rather inefficient because of relatively high proportions of false negative and false positive smears. To evaluate the efficiency of high-risk human papillomavirus (hrHPV) testing, by GP5؉/6؉ PCR-enzyme immunoassay (EIA), in conjunction with cytology (Intervention Group) to that of the classical cytology (Control Group), we initiated the Population Based Screening Study Amsterdam (POBASCAM). POBASCAM is a population-based randomized controlled trial for implementation of hrHPV testing in cervical screening. The outcome measure is the proportion of histologically confirmed >CIN3 lesions in each study arm up to and including the next screening round after 5 years. We present the design, methods and baseline data of POBASCAM. When, in the next 5 years, the follow-up will be completed, the data obtained will be used in model studies, including a cost-effectiveness study, to advise the Dutch Ministry of Public Health in deciding whether cervical screening should be based on combined hrHPV and cytology testing instead of cytology alone. Between January 1999 and September 2002, 44,102 women (mean age ‫؍‬ 42.8 years; range ‫؍‬ 29 -61) that participated in the regular Dutch screening program were included in our study. In the Intervention Group the distribution of cytology and hrHPV by cytology class was as follows: normal cytology 96.6% (3.6% hrHPV positive); borderline and mild dyskaryosis (BMD) 2.5% (34.6% hrHPV positive); and moderate dyskaryosis or worse (>BMD) 0.8% (88.3% hrHPV positive), i.e., 0.4% moderate dyskaryosis (82.9% hrHPV positive), 0.3% severe dyskaryosis (92.5% hrHPV positive), 0.1% carcinoma in situ (95.2% hrHPV positive), <0.1% suspected for invasive cancer (hrHPV positive 100.0%). In the Control Group 96.5% of the women had normal cytology, 2.4% BMD and 0.8% >BMD, i.e., 0.4% moderate dyskaryosis, 0.3% severe dyskaryosis, 0.1% carcinoma in situ, <0.1% suspected for invasive cancer. The presence of hrHPV was age-dependent, decreasing from 12.0% at 29 -33 years to 2.4% at 59 -61 years. Among women with a positive hrHPV test, the prevalence of BMD was age-dependent ranging from 20.2% at 29 -33 years to 7.8% at 54 -58 years. In contrast, the risk of >BMD of 13.7% among women with a positive hrHPV test was not age-dependent. Our study indicates that large-scale hrHPV testing by GP5؉/6؉ PCR-EIA in the setting of population-based cervical screening is practically feasible, is accepted by both participating women and general practitioners and yields highly reproducible results.

To evaluate the clinical significance of HPV genotyping for the prediction of progressive cervical intraepithelial neoplasia (CIN) in women with cytomorphologically abnormal smears, a prospective, blind, non-intervention study was performed. A total of 342 patients screened with cytomorphologically abnormal cervical smears were monitored every 3-4 months by cervical cytology, colposcopy and HPV testing using PCR. Women with progressive CIN disease were defined as patients developing lesions with a colposcopic impression of CIN III over more than 2 quadrants or resulting in a cytological smear equivalent to Pap 5. These patients were subsequently treated according to standard procedures. If any doubt arose about the true status of the patients (n = 75) these patients were censored and biopsied. The mean follow-up time was 16.5 months (range 3-36 months). Nineteen women showed progressive CIN disease and all appeared to be continuously HPV-positive from the start of the study. At biopsy, all these patients were histologically classified as CIN III. Seventeen of these women were positive for high-risk HPV types. Two cases were classified as still unidentified HPV. No progression was seen in the absence of HPV DNA or in the presence of low-risk HPV types. In life-table analysis the cumulative rate of progressive, histologically verified CIN disease was 17% after 36 months. Further analyses showed that other risk factors such as age, sexarche, number of sexual partners or smoking hardly influenced the effect of HPV on progression. The results show that the continuous presence of high-risk HPV types in women with cytomorphologically abnormal smears is a strong marker for progressive CIN disease.

The relation between human papillomavirus type 16 (HPV 16) viral load in cervical scrapes and development of highgrade cervical intraepithelial neoplasia (CIN II or III) was studied in a nested case-control study of women with normal cytology (group A) and in a cohort of women with abnormal cytology (group B). HPV 16 DNA load was determined using a quantitative real-time PCR assay. In group A, case women (women with CIN II/III, n ‫؍‬ 12) had a significantly higher viral load than control women (women with CIN < I, n ‫؍‬ 47). This resulted in an increased relative risk of women with the 50% highest viral load for development of CIN II/III (OR 7.7; CI 1.6 -33). In group B, women with CIN II/III (n ‫؍‬ 38) had a significantly higher viral load than women with CIN < I (n ‫؍‬ 25). Women with the 50% highest viral load had an increased relative risk of CIN II/III (OR 3.2; CI 1.1-9.3) and a decreased chance of both viral clearance and cytologic regression. Our data suggest that in women with normal cytology an increased HPV 16 load confers an increased risk of developing a CIN lesion. A sustained high viral load is subsequently informative for progression to a high-grade CIN lesion. © 2002 Wiley-Liss, Inc. Key words: HPV 16 load; normal cytology; abnormal cytology; CIN II/III; viral clearanceA multitude of studies have established infection with high-risk human papillomavirus (HPV) types as a necessary cause of cervical cancer. 1,2 On the basis of these studies, it has been proposed that testing for the presence of high-risk HPV DNA in cervical scrapes as an adjunct of cervical cytology can be of great value in a variety of clinical settings. 3 Persistence of high-risk HPV DNA appeared to be a prerequisite for the development of high-grade CIN lesions. 4,5 Nevertheless, the far majority of high-risk HPV infections are transient and will either not give rise to a lesion or at most lead to spontaneously regressing, low-grade cervical intraepithelial neoplasia (CIN). 6,7 Hence, there is a strong need for additional markers that predict the outcome of high-risk HPV infection with increased specificity. Using semiquantitative approaches, several studies have implicated that the amount of highrisk HPV DNA present in the cervical scrape, the viral load, can be of value to predict prevalent or incident high-grade CIN. 8 -16 This has recently been substantiated by a fully quantitative, real-time PCR-based retrospective study on cytomorphologically normal archival smears of women who developed cervical carcinoma in situ (CIS). It appeared that women with the highest HPV 16 load were at increased risk of developing CIS. 17 However, with the aid of a fully quantitative method, no studies so far have addressed whether viral load could also be informative for women with abnormal cervical scrapes or to predict future clearance of high-risk HPV infections. Using frozen, freshly collected cervical scrapes collected from well-defined cohorts of women with normal 18,19 and abnormal cytology, 5 we addressed the following questions. First...

No abstract

Women not attending cervical screening programs are at increased risk of cervical cancer. We investigated in these nonresponders to what extent offering self-sampling devices for cervicovaginal brushes for high-risk human papillomavirus (hrHPV) testing would induce participation and, if so, what the yield of precursor (i.e. CIN2 or worse) lesions following self-sampling would be. In addition, we assessed screening history of participants and costs per detected high-grade CIN2 or worse ("CIN2+") lesion in comparison to the regular program in the Netherlands. Nonresponders received a device for hrHPV testing (self-sampling group, n=2,546) or an extra recall for conventional cytology (control group, n=284). The percentage of self-sampling responders were compared with responders in the recall group. hrHPV positive self-sampling responders were invited for cytology and colposcopy. CIN2+ yield and costs per detected CIN2+ were evaluated. Active response was higher in the self-sampling than in the control group (34.2 vs. 17.6%; p<0.001). hrHPV positive self-sampling responders were less likely to have a prior screening history than screening participants (p<0.001), indicating that they are regular nonresponders. hrHPV prevalence was similar (8.0 vs. 6.8%; p=0.11), but CIN2+ yield was higher in self-sampling responders compared to screening participants (1.67 vs. 0.97%; OR=2.93, 95% CI 1.48-5.80; p=0.0013). Costs per CIN2+ lesion detected via self-sampling were in the same range as those calculated for conventional cytological screening (euro 8,836 vs. euro 7,599). Offering self-sampling for hrHPV testing in nonresponders is an attractive adjunct to effectively increase population coverage of screening without the adverse effect of markedly increased costs per detected CIN2+ lesion.