Primary HPV DNA screening with cytology triage is more sensitive than conventional screening. Among women aged 35 years or older, primary HPV DNA screening with cytology triage is also more specific than conventional screening and decreases colposcopy referrals and follow-up tests.

Objective To assess the performance and impact of primary human papillomavirus (HPV) DNA screening with cytology triage compared with conventional cytology on cervical cancer and severe pre-cancerous lesions. Design Randomised trial. Setting Population based screening programme for cervical cancer in southern Finland in 2003-5. Participants 58 076 women, aged 30-60, invited to the routine population based screening programme for cervical cancer. Interventions Primary HPV DNA test (hybrid capture II) with cytology triage if the result was positive or conventional cytological screening (reference). Main outcome measures Rate of cervical cancer, cervical intraepithelial neoplasia (CIN) grade III, and adenocarcinoma in situ (as a composite outcome referred to as CIN III+) during 2003-7 through record linkage between files from the screening registry and the national cancer registry. Results In the HPV and conventional arms there were 95 600 and 95 700 woman years of follow-up and 76 and 53 cases of CIN III+, respectively (of which six and eight were cervical cancers). The relative rate of CIN III+ in the HPV arm versus the conventional arm was 1.44 (95% confidence interval 1.01 to 2.05) among all women invited for screening and 1.77 (1.16 to 2.74) among those who attended. Among women with a normal or negative test result, the relative rate of subsequent CIN III+ was 0.28 (0.04 to 1.17). The rate of cervical cancer between arms was 0.75 (0.25 to 2.16) among women invited for screening and 1.98 (0.52 to 9.38) among those who attended. Conclusions When incorporated into a well established organised screening programme, primary HPV screening with cytology triage was more sensitive than conventional cytology in detecting CIN III+ lesions. The number of cases of cervical cancer was small, but considering the high probability of progression of CIN III the findings are of importance regarding cancer prevention.Trial registration Current Controlled Trials ISRCTN23885553.

The role of high-risk human papillomavirus (hrHPV) testing in primary cervical screening has not been established. We generated a randomised evaluation design ultimately to clarify whether primary hrHPV testing implemented into routine screening can bring increase in the programme effectiveness. The aim of the present report on first-year results was to assess the cross-sectional relative validity parameters for routine hrHPV screening, in comparison with conventional screening. An equal number of women invited to routine screening was randomly allocated to primary hrHPV screening (n ¼ 7060) and to cytological screening (n ¼ 7089). In the hrHPV screening arm, after a single positive hrHPV test result, the need of colposcopy referral was determined by a cytological triage test. Compared with the conventional arm, more colposcopy referrals were made in the hrHPV screening arm (relative risk 1.51, confidence interval 95% 1.03 -2.22). Specificity of the primary screening with sole hrHPV test (91.5 -92.1%) was much lower than that with the cytology triage (98.7 -99.3%), which was not quite as specific as screening with conventional cytology (99.2 -99.6%). Compared with conventional cytology, primary screening with hrHPV test results in increased cross-sectional relative sensitivity at the level of all positive lesions at the cost of substantial loss in specificity. With cytology triage, the specificity improves to the level of conventional cytology.

We compared test sensitivity (in terms of prevented cancers) and overdiagnosis (in terms of non-progressive pre-invasive lesions) between the human papillomavirus test (HPV test, Hybrid Capture 2) and the traditional Pap test in routine screening for cervical cancer. The design was a randomised (1:1) health services study in Finland with intake between 2003 and 2007. We estimated sensitivity by the incidence method within one screening round. Overdiagnosis was based on the rate of cervical intraepithelial Grade 3 (CIN3) lesions diagnosed at screen and during the following interval. Out of 203,788 randomised women 132,298 attended (65% in both study arms) and 600,753 person-years accumulated among attenders up to the end of 2010. In all attenders, 34 invasive cervical cancers and 288 CIN3 lesions were diagnosed at screen or during the following interval. The interval cancer incidence was 2.5/10 5 person-years (sensitivity 0.87) and 1.4 (sensitivity 0.93) in the HPV arm and Pap test arm, respectively. The rate of CIN3 lesions was 57.1 and 38.8, respectively. In conclusion, sensitivity of HPV testing was similar to that of Pap testing but caused more overdiagnosis. Therefore, implementation of HPV testing needs to be reconsidered especially in countries with well organised programmes.Recommendations concerning new screening tests for cervical cancer are mostly based on cross-sectional studies and on detection rates of pre-invasive lesions. 1-5 The few follow-up studies have focused on pre-invasive lesions and on the length of reassurance that a negative test provides. 6-10 Only few studies have had emphasis on public health aspects. 11,12 The purpose of screening is to prevent invasive cervical cancer and the demonstration of this effect requires follow-up for incident invasive cancers after the screen. In fact, detection (at screen) of pre-invasive lesions results in both benefit and harm; benefit through preventing some of the lesions from progressing to invasive cancer, and harm by detecting also such pre-invasive lesions that would never have progressed to invasive cancers. These two types of pre-invasive lesions cannot be separated and thus, both types have to be treated if diagnosed.Sensitivity measures a screening test's ability to correctly identify unrecognised disease. It can be estimated in several ways. The most common way is called the detection method 4 which is based on screen detected lesions, both pre-invasive and invasive ones. However, the sensitivity estimate is usually biased and too big (closer to one) due to overdiagnosis of the detection of pre-invasive lesions. Sensitivity can also be estimated by the incidence method 13 that is based on failures of screening.The purpose of the present study was to compare the human papillomavirus (HPV) test to the traditional Pap test in cervical cancer screening in terms of sensitivity (detection of progressive lesions) and overdiagnosis (detection of nonprogressive lesions). Material and methodsIn Finland, women between 30 and 60 years of age (sometimes ...

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BackgroundCervical cancer screening programmes have markedly reduced the incidence and mortality rates of the disease. A substantial amount of deaths from the disease could be prevented further by organised screening programmes or improving currently running programmes.Methods/DesignWe present here a randomised evaluation trial design integrated to the Finnish cervical cancer screening programme, in order to evaluate renewal of the programme using emerging technological alternatives. The main aim of the evaluation is to assess screening effectiveness, using subsequent cancers as the outcome and screen-detected pre-cancers as surrogates. For the time being, approximately 863,000 women have been allocated to automation-assisted cytology, human papillomavirus (HPV) DNA testing, or to conventional cytology within the organised screening programme. Follow-up results on subsequent cervical cancers will become available during 2007–2015.DiscussionLarge-scale randomised trials are useful to clarify effectiveness and cost-effectiveness issues of the most important technological alternatives in the screening programmes for cervical cancer.

A persistent high-risk human papillomavirus (hrHPV) infection is a necessary condition for developing a cervical intraepithelial neoplasia and cervical cancer. The viral aetiology in cervical carcinogenesis has stimulated attempts to use HPV DNA detection in cervical cancer screening. In Finland there is an ongoing study assessing the benefits of primary HPV DNA testing in the setting of centrally organised mass screening for cervical cancer. Here we present the age-specific prevalence of hrHPV infection and associated sociodemographic factors of 16,895 women aged 25-65 years attending the 5-yearly cervical cancer screening between years 2003 and 2004. The overall hrHPV prevalence rate was 7.5%. The peak prevalence at the age group of 25-29 was 24.1% decreasing steadily thereafter to approximately 2.9% in women aged 65 years. Young age and marital status were the main determinants for oncogenic HPV types. Our study confirms the inverse relationship between age and hrHPV prevalence reported in many developed countries. As our prevalence rates and hence background risk for cervical cancer are not lower than in other European countries, it is likely that our lowest cervical cancer burden in Europe is due to health care actions justifying the organised cervical cancer screening. ' 2008 Wiley-Liss, Inc.Key words: high-risk HPV; prevalence; age; cervical cancer; screeningIn Finland an organised nationwide screening programme has been running over 40 years, reducing the age-adjusted incidence and mortality of cervical cancer by 80%, 1 incidence rate being about 4 cases per 100,000 woman-years nowadays. Nevertheless, there are still about 160 new cancer cases every year making the cervical cancer the third most common gynaecological cancer, but 20th of all female cancers, in Finland. 2 However, during the last 10 years, the cervical cancer incidence rate has been increasing among young target ages of the screening programme which is mainly due to inadequate attendance rates to the screening programme. 1 Cohort effects related to changes in exposure to risk factors such as sexual behaviour and smoking habits may also partly explain the increase.Despite the enormous impacts of cytology based screening on cervical cancer incidence and mortality rates in Finland, the Pap test has its limitations as errors in sample taking and in interpretation. As it is known that a persistent high-risk human papillomavirus (hrHPV) infection is a necessary condition for developing a cervical intraepithelial neoplasia (CIN) and cervical cancer 3 and moreover, hrHPV DNA is found in virtually all cases of cervical cancer, 4,5 HPV DNA detection has been suggested for cervical cancer screening as the primary test.To find out whether using HPV DNA detection can bring increase into the routine population-based screening programme effectiveness in Finland, a commercial hrHPV detection test, Hybrid Capture 2 (HC 2, Digene Corporation, Gaithersburg, MD), has been implemented into cervical cancer screening programme as the primary screening test sinc...

We present data on test positivity, relative sensitivity, rates of detection and relative specificity for primary human papillomavirus (HPV) testing with different cutoff levels for test positivity, in comparison to conventional cytology. In 2003In -2004,438 women were screened primarily with Hybrid Capture 2 (HC 2) assay, a test for oncogenic HPV DNA, and 21,446 with conventional cytology within the organised screening programme in Finland. A cytological triage test was performed for the HPV positives. Women with cytology equal to low grade squamous intraepithelial lesion (LSIL) or worse were referred for colposcopy. The relative sensitivity measured as relative risk (RR) of any cervical intraepithelial neoplasia (CIN) or cancer was 1.58 for the HPV test at the relative light units (rlu) ratio cutoff 1.00, in comparison to cytology. With the cutoff 3.00, all CIN 21 lesions were detected. With cutoff 10.00, 2 of the 22 CIN 31 lesions were missed. Relative specificity for HPV screening for any CIN was 92.6% at cutoff 1.00, 94.6% at cutoff 3.00 and 96.3% at cutoff 10.00. For CIN 31 specificity estimates for these cutoffs were 92.1%, 94.1% and 95.8%, respectively. Used for routine screening as the sole test, the HPV test cutoff can be increased from the level recommended for clinical use. With HC 2, the detection rate at rlu ratio cutoff 10.00 is still at the level of highquality conventional screening. At that level, the false positive rate is reduced by about half and the specificity of the HPV test becomes equal to the average specificity of conventional cytology. ' 2008 Wiley-Liss, Inc.Key words: cervical cancer; routine screening; HPV DNA testing; Hybrid Capture 2; rlu ratioThe conventional Papanicolaou (Pap) test and its modern modifications, i.e., liquid-based or automation-assisted cytological test, are effective methods for cervical cancer prevention. In most of the world, however, implementation of cytological tests into organised screening programmes has not succeeded optimally, and thus, cervical cancer remains a major burden in many countries, especially in the developing world. 1,2 Non-cytological tests, such as visual inspection aided with acetic acid or iodine and human papillomavirus (HPV) DNA or RNA detection tests, have been proposed as alternatives for cytology in population-based screening.Theoretically, an optimal screening test is both highly specific and highly sensitive. In reality, we need to compromise between specificity and sensitivity. In population-based screening, specificity is of high importance, as it basically determines how costly the program is and how much unwanted adverse effects (anxiety, repetitive and confirmatory tests as well as unnecessary treatments) it causes to the generally healthy population. In several studies, the Hybrid Capture 2 (HC 2) test for oncogenic HPV DNA at standard cutoff level for test positivity has shown to be of lower specificity than the traditional cytology. [3][4][5] Cytological triage test offers means to improve the specificity of the screeni...