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      Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study

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          Abstract

          Objective To obtain large scale and generalisable data on the long term predictive value of cytology and human papillomavirus (HPV) testing for development of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+).

          Design Multinational cohort study with joint database analysis.

          Setting Seven primary HPV screening studies in six European countries.

          Participants 24 295 women attending cervical screening enrolled into HPV screening trials who had at least one cervical cytology or histopathology examination during follow-up.

          Main outcome measure Long term cumulative incidence of CIN3+.

          Results The cumulative incidence rate of CIN3+ after six years was considerably lower among women negative for HPV at baseline (0.27%, 95% confidence interval 0.12% to 0.45%) than among women with negative results on cytology (0.97%, 0.53% to 1.34%)). By comparison, the cumulative incidence rate for women with negative cytology results at the most commonly recommended screening interval in Europe (three years) was 0.51% (0.23% to 0.77%). The cumulative incidence rate among women with negative cytology results who were positive for HPV increased continuously over time, reaching 10% at six years, whereas the rate among women with positive cytology results who were negative for HPV remained below 3%.

          Conclusions A consistently low six year cumulative incidence rate of CIN3+ among women negative for HPV suggests that cervical screening strategies in which women are screened for HPV every six years are safe and effective.

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          Most cited references27

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          Overview of the European and North American studies on HPV testing in primary cervical cancer screening.

          Several studies suggest that HPV testing is more sensitive than cytology in primary cervical screening. These studies had different designs and were reported in different ways. Individual patient data were collected for all European and North American studies in which cytology was routinely performed and HPV testing was included as an additional parallel test. More than 60,000 women were included. The sensitivity and specificity of HPV testing were compared with routine cytology, both overall and for ages <35, 35-49 and 50+. The age-specific prevalence of high risk HPV (hr-HPV) was also analysed. HPV testing was substantially more sensitive in detecting CIN2+ than cytology (96.1% vs. 53.0%) but less specific (90.7% vs. 96.3%). The sensitivity of HPV testing was similar in all studies carried out in different areas of Europe and North America, whereas the sensitivity of cytology was highly variable. HPV sensitivity was uniformly high at all ages, whereas the sensitivity of cytology was substantially better in women over the age of 50 than in younger women (79.3% vs. 59.6%). The specificity of both tests increased with age. Positivity rates for HPV testing in women without high-grade CIN were region dependent. These results support the use of HPV testing as the sole primary screening test, with cytology reserved for women who test HPV positive. Large demonstration projects are needed to fully evaluate this strategy. Copyright 2006 Wiley-Liss, Inc.
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            Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer.

            To determine whether testing for DNA of oncogenic human papillomaviruses (HPV) is superior to the Papanicolaou (Pap) test for cervical-cancer screening, we conducted a randomized trial comparing the two methods. We compared HPV testing, using an assay approved by the Food and Drug Administration, with conventional Pap testing as a screening method to identify high-grade cervical intraepithelial neoplasia in women ages 30 to 69 years in Montreal and St. John's, Canada. Women with abnormal Pap test results or a positive HPV test (at least 1 pg of high-risk HPV DNA per milliliter) underwent colposcopy and biopsy, as did a random sample of women with negative tests. Sensitivity and specificity estimates were corrected for verification bias. A total of 10,154 women were randomly assigned to testing. Both tests were performed on all women in a randomly assigned sequence at the same session. The sensitivity of HPV testing for cervical intraepithelial neoplasia of grade 2 or 3 was 94.6% (95% confidence interval [CI], 84.2 to 100), whereas the sensitivity of Pap testing was 55.4% (95% CI, 33.6 to 77.2; P=0.01). The specificity was 94.1% (95% CI, 93.4 to 94.8) for HPV testing and 96.8% (95% CI, 96.3 to 97.3; P<0.001) for Pap testing. Performance was unaffected by the sequence of the tests. The sensitivity of both tests used together was 100%, and the specificity was 92.5%. Triage procedures for Pap or HPV testing resulted in fewer referrals for colposcopy than did either test alone but were less sensitive. No adverse events were reported. As compared with Pap testing, HPV testing has greater sensitivity for the detection of cervical intraepithelial neoplasia. (Current Controlled Trials number, ISRCTN57612064 [controlled-trials.com].). Copyright 2007 Massachusetts Medical Society.
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              Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial.

              Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented. Women aged 29-56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131. 8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (> or =6.5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15-151; p=0.007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28-72; p=0.001). The number of CIN3+ lesions over the two rounds did not differ between groups. The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3+ lesions. Earlier detection of such lesions could permit an extension of the screening interval.

                Author and article information

                Contributors
                Role: professor
                Role: researcher
                Role: professor and head of department
                Role: professor
                Role: clinical consultant and honorary senior lecturer
                Role: researcher
                Role: researcher
                Role: research fellow
                Role: researcher
                Role: professor
                Role: professor and head of department
                Role: professor
                Role: professor
                Role: professor and head of section
                Journal
                BMJ
                bmj
                BMJ : British Medical Journal
                BMJ Publishing Group Ltd.
                0959-8138
                1468-5833
                2008
                2008
                13 October 2008
                : 337
                : a1754
                Affiliations
                [1 ]Lund University, Medical Microbiology, University Hospital MAS, 205 02 Malmö, Sweden
                [2 ]Department of Public Health, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, Netherlands
                [3 ]CHU Reims, Service d’Anatomie Pathologique, INSERM UMR-S 903, Laboratoire Pol Bouin, Reims, France
                [4 ]Department of Obstetrics and Gynaecology, Teaching Hospital Wolfsburg, Germany
                [5 ]Cancer Research UK, Wolfson Institute of Preventive Medicine, London
                [6 ]Institute of Cancer Epidemiology, Danish Cancer Society, DK-2100, Copenhagen, Denmark
                [7 ]Catalan Institute of Oncology, Hospital Duran i Reynals, Barcelona, Spain
                [8 ]Gynecologic Clinic, Rigshospitalet, Copenhagen University Hospital, Denmark
                [9 ]CIBER Epidemiologia y Salud Pública (CIBERESP), Spain
                [10 ]Section of Experimental Virology, Institute of Medical Virology, University Hospital of Tübingen, Germany
                Author notes
                Correspondence to: J Dillner joakim.dillner@ 123456med.lu.se
                Article
                dilj569939
                10.1136/bmj.a1754
                2658827
                18852164
                22097945-d7ab-451d-9d54-35cb18f1cf65
                © Dillner et al 2008

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 July 2008
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                Medicine
                Medicine

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