Cost-effectiveness of primary human papillomavirus triage approaches among vaccinated women in Norway: A model-based analysis.

As Norway considers revising triage approaches following their first adolescent cohort with human papillomavirus (HPV) vaccination entering the cervical cancer screening program, we analyzed the health impact and cost-effectiveness of alternative primary HPV triage approaches for women initiating cervical cancer screening in 2023. We used a multimodeling approach that captured HPV transmission and cervical carcinogenesis to evaluate the health benefits, harms and cost-effectiveness of alternative extended genotyping and age-based triage strategies under five-yearly primary HPV testing (including the status-quo screening strategy in Norway) for women born in 1998 (ie, age 25 in 2023). We examined 35 strategies that varied alternative groupings of high-risk HPV genotypes ("high-risk" genotypes; "medium-risk" genotypes or "intermediate-risk" genotypes), number and types of HPV included in each group, management of HPV-positive women to direct colposcopy or active surveillance, wait time for re-testing and age at which the HPV triage algorithm switched from less to more intensive strategies. Given the range of benchmarks for severity-specific cost-effectiveness thresholds in Norway, we found that the preferred strategy for vaccinated women aged 25 years in 2023 involved an age-based switch from a less to more intensive follow-up algorithm at age 30 or 35 years with HPV-16/18 genotypes in the "high-risk" group. The two potentially cost-effective strategies could reduce the number of colposcopies compared to current guidelines and simultaneously improve health benefits. Using age to guide primary HPV triage, paired with selective HPV genotype and follow-up time for re-testing, could improve both the cervical cancer program effectiveness and efficiency.

Divergent effects of switching from cytology to HPV-based screening in the Nordic countries.

BACKGROUND: Cervical cytology has been the primary method of cervical cancer screening for decades. Tests that detect viral HPV are shown in several randomized trials to provide better protection against cancer compared with cytology. HPV-based screening has been implemented alongside cytology in the Nordic countries for several years. The aim of this study was to compare cytology and HPV-based screening in the colposcopy referrals and detection rates of cervical lesions. METHODS: Individual-level screening data from Finland, Iceland, Norway and Sweden were harmonized and aggregated locally. We utilized data for tests taken during years 2015-17 and biopsies taken during years 2015-19 to allow 24 months of follow-up. Age-standardized estimates and age-adjusted risk ratios for six different outcomes of screening management were calculated. RESULTS: The age-standardized colposcopy rates were higher in HPV-based testing compared with cytology in Finland (3.5% vs. 0.9%) and Norway (6.0% vs. 4.1%) but lower in Sweden (3.7% vs. 4.9%). The relative detection rate of cervical intraepithelial neoplasia grade 2 and above in HPV-based testing compared with cytology was highest in Finland (RR 2.37, 95% CI 2.13-2.63) and Norway (RR 1.66, 95% CI 1.57-1.72) while in Sweden the difference was not statistically significant (RR 0.98, 95% CI 0.95-1.00). CONCLUSIONS: The effects of implementing HPV screening varied by country as different screening algorithms were implemented. HPV-based screening increases colposcopy rates mainly through referrals from increased repeat testing and detection rate is therefore significantly higher compared with cytology. Monitoring of these indicators in subsequent rounds of HPV-based screening remains essential.

Livmorhalsprøvetaking i primærhelsetjenesten.

BACKGROUND: In Norway, approximately 360 000 cervical screening samples were taken in 2020, of which 11 000 were registered as inadequate. We therefore wished to investigate doctors' knowledge of cervical sample-taking in the primary health service. MATERIAL AND METHOD: An anonymous survey on cervical sample-taking was sent by email to around 4 700 members of the Norwegian College of General Practice in September 2021. RESULTS: Of the 1 039 doctors who responded to the survey, 820 (79 %) reported that they always indicate the reason for taking the sample in the requisition form, and 898 (86 %) reported that they avoid taking a sample during menstruation. Only one in three doctors (343) correctly indicated the location of the squamocolumnar junction in postmenopausal women. In response to a question aimed at users of the ThinPrep method, which is particularly sensitive to sampling errors, 426 out of 697 (61 %) answered that they either avoid using a lubricant or use a water-based lubricant, while only 35 % of the doctors responded that they stop taking the sample if bleeding occurs. INTERPRETATION: The results show that although many doctors have satisfactory knowledge, a continuous focus on cervical sample-taking is essential. Correct sampling and knowledge of anatomical factors in postmenopausal women may be significant for reducing the number of inadequate samples.

Switching clinic-based cervical cancer screening programs to human papillomavirus self-sampling: A cost-effectiveness analysis of vaccinated and unvaccinated Norwegian women.

Several countries have implemented primary human papillomavirus (HPV) testing for cervical cancer screening. HPV testing enables home-based, self-collected sampling (self-sampling), which provides similar diagnostic accuracy as clinician-collected samples. We evaluated the impact and cost-effectiveness of switching an entire organized screening program to primary HPV self-sampling among cohorts of HPV vaccinated and unvaccinated Norwegian women. We conducted a model-based analysis to project long-term health and economic outcomes for birth cohorts with different HPV vaccine exposure, that is, preadolescent vaccination (2000- and 2008-cohorts), multiage cohort vaccination (1991-cohort) or no vaccination (1985-cohort). We compared the cost-effectiveness of switching current guidelines with clinician-collected HPV testing to HPV self-sampling for these cohorts and considered an additional 44 strategies involving either HPV self-sampling or clinician-collected HPV testing at different screening frequencies for the 2000- and 2008-cohorts. Given Norwegian benchmarks for cost-effectiveness, we considered a strategy with an additional cost per quality-adjusted life-year below $55 000 as cost-effective. HPV self-sampling strategies considerably reduced screening costs (ie, by 24%-40% across cohorts and alternative strategies) and were more cost-effective than clinician-collected HPV testing. For cohorts offered preadolescent vaccination, cost-effective strategies involved HPV self-sampling three times (2000-cohort) and twice (2008-cohort) per lifetime. In conclusion, we found that switching from clinician-collected to self-collected HPV testing in cervical screening may be cost-effective among both highly vaccinated and unvaccinated cohorts of Norwegian women.

HPV self-sampling among long-term non-attenders to cervical cancer screening in Norway: a pragmatic randomised controlled trial.

BACKGROUND: Cervical cancer screening participation is suboptimal in most settings. We assessed whether human papillomavirus (HPV) self-sampling may increase screening participation among long-term non-attenders in Norway. METHODS: A pragmatic randomised controlled trial with participation as the primary outcome was initiated in the national cervical screening programme in March 2019. A random sample of 6000 women aged 35-69 years who had not attended screening for at least 10 years were randomised 1:1:1 to receive either (i) a reminder to attend regular screening (control), (ii) an offer to order a self-sampling kit (opt-in) for HPV testing or (iii) a self-sampling kit unsolicited (send-to-all) for HPV testing. RESULTS: Total participation was 4.8%, 17.0% and 27.7% among control, opt-in and send-to-all (P < 0.0001; participation difference (%) send-to-all vs. control: 22.9 (95%CI: 20.7, 25.2); opt-in vs. control: 12.3 (95%CI: 10.3, 14.2); send-to-all vs. opt-in: 10.7 (95% CI: 8.0, 13.3)). High-risk HPV was detected in 11.5% of self-samples and 9.2% of clinician-collected samples (P = 0.40). Most women (92.5%) who returned a positive self-sample attended the clinic for triage testing. Of the 933 women screened, 33 (3.5%) had CIN2 + (1.1%, 3.7%, 3.8% among control, opt-in, and send-to-all, respectively), and 11 (1.2%) had cervical cancer (0%, 1.2%, 1.3% among control, opt-in, send-to-all, respectively). CONCLUSION: Opt-in and send-to-all self-sampling increased screening participation among long-term, higher-risk non-attenders. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03873376.

Does Women's Screening History Have Any Impact on Mammography Screening Attendance After Tailored Education?: A Systematic Review and Meta-analysis.

BACKGROUND: Many ethnic minority women have low attendance at breast cancer screening. OBJECTIVES: This brief report explores whether women's screening histories impact mammography screening attendance after tailored education. RESEARCH DESIGN: Systematic searches were conducted in 5 databases. Randomized controlled trials of educational interventions tailored to ethnic minority women that measured attendance at mammography screening were eligible for inclusion. Data extraction and risk of bias assessment were performed independently. Data were combined in a meta-analysis by using random effects models. Heterogeneity was estimated by using I2 statistics. RESULTS: Six studies with 3521 women were eligible for inclusion. The D+L pooled risk ratio (RR) for mammography attendance for never screened participants was 1.54 (95% confidence interval, 1.24-1.91; P<0.001), with low heterogeneity (I2=27.1%, P=0.231). The D+L pooled risk ratio for attendance for ever screened participants was 1.26 (95% confidence interval, 1.11-1.43; P<0.001), with low heterogeneity (I2=35.5%, P=0.213). CONCLUSIONS: Tailored education increased attendance at mammography by 54% among never screened women and 26% among ever screened women. Although these findings must be interpreted with caution, the findings suggest that women's screening history is an important and ignored variable that affects how effective tailored education is on mammography screening attendance.

Real-world data on cervical cancer risk stratification by cytology and HPV genotype to inform the management of HPV-positive women in routine cervical screening.

BACKGROUND: HPV16/18 detection may improve cervical cancer risk stratification and better guide which HPV-positive women warrant immediate colposcopy/biopsy. We estimated risks of cervical precancer and cancer by HPV genotype and cytology during the implementation phase of primary HPV testing in Norway. METHODS: A total of 3111 women, aged 34-69 years, testing HPV-positive at baseline and undergoing cytology testing from February 2015 to April 2018 had data available for analysis. Risk estimates with 95% confidence intervals (95%CIs) of cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) were estimated for cytology results and HPV genotypes (HPV16, HPV18, and other high-risk HPV). RESULTS: CIN3+ risks were higher for HPV16/18 than other high-risk HPV genotypes. Among women with any cytologic abnormality [atypical squamous cells of undetermined significance or worse], immediate risks were 57.8% (95%CI = 53.0-62.6%) for HPV16, 40.2% (95%CI = 32.3-49.2%) for HPV18, and 31.4% (95%CI = 28.7-34.3%) for other high-risk HPV. Among those with normal cytology, CIN3+ risks were 19.9% (95%CI = 15.0-26.1%) for HPV16 positives, 10.8% (95%CI = 5.6-20.5%) for HPV18 positives, and 5.5% (95%CI = 4.2-7.1%) for other high-risk HPV. CONCLUSIONS: The benefits and harms of managing women based on HPV positivity and cytology results can be better balanced by inclusion of HPV genotyping in screening and choosing more conservative management for other high-risk HPV compared to HPV16/18.

Adherence to international recommendations in the governance and organisation of Nordic cervical cancer screening programmes.

INTRODUCTION: Screening has been the primary reason for the decline in the incidence and mortality of cervical cancer in the Nordic countries since the beginning of screening in the 1960s. Recently, the incidence of cervical cancer has increased in the Nordic countries indicating the need to look closely at possibilities for further improvement in screening. This article provides an overview of cervical cancer screening programmes in the Nordic countries and whether the programmes adhere to international recommendations. MATERIALS AND METHODS: Relevant and unambiguous screening recommendations were extracted from applicable literature and classified into legal framework, governance, organisation, and monitoring and evaluation. The up-to-date status of screening programmes and adherence to selected recommendations was gathered from official documentation and co-authors representing cervical cancer screening programmes in all the Nordic countries. RESULTS: A total of 168 recommendations were extracted and 54 of them were considered to be unambiguous and relevant. Forty-nine recommendations were included after synthesising similar recommendations. All Nordic countries adhere to recommendations related to legal framework, but adherence was lower with recommendations related to governance and organisation of screening. Monitoring and evaluation are also areas where adherence to recommendations could be improved. CONCLUSIONS: The Nordic cervical cancer screening programmes have substantially decreased cancer burden despite not fully adhering to many of the recommendations. The presented gaps in adherence suggest that there is room for improvement in the screening programmes. Establishing clearer governance structures would still increase the ability to manage changes such as implementing HPV testing as the primary screening method or modifying the programme when HPV vaccinated cohorts of women enter the target age for screening.

Psychological effect of cervical cancer screening when changing primary screening method from cytology to high-risk human papilloma virus testing.

From 2015, Norway has implemented high-risk human papilloma virus (hrHPV) testing in primary screening for cervical cancer. Women aged 34-69 years, living in four counties, have been pseudo-randomly assigned (1:1 randomization) to either hrHPV testing every 5 years (followed by cytology if hrHPV is positive), or cytology testing every 3 years (followed by hrHPV testing if low-grade cytology is detected). We compared anxiety and depression scores among participants by screening arm and results. In total, 1,008 women answered a structured questionnaire that included the validated Patient Health Questionnaire-4 (PHQ-4). The Relative Risk Ratio (RRR) of mild vs. normal anxiety and depression scores, and moderate/severe vs. normal anxiety and depression scores, were estimated by multinomial logistic regression with 95% confidence intervals (95% CIs). Compared to women who were screened with cytology, women randomized to hrHPV testing were not more likely to have mild anxiety and depression scores (RRR 0.96, CI 0.70-1.31) nor more likely to have moderate/severe anxiety and depression scores (RRR 1.14, CI 0.65-2.02). Women with five different combinations of abnormal screening test results were not more likely to have mild or moderate/severe vs. normal anxiety and depression scores than women with normal screening results. The likelihood of having abnormal long-term (4-24 months after the screening) anxiety or depression scores among women 34 years and older was not affected by screening method or screening results. The results of our study suggest that a change to hrHPV testing in primary screening would not increase psychological distress among participants.

NordScreen - an interactive tool for presenting cervical cancer screening indicators in the Nordic countries.

Introduction: Quality assurance and improvement of cancer screening programs require up-to-date monitoring systems and evidence-based indicators. National quality reports exist but the definition and calculation of indicators vary making comparisons between countries difficult. The aim is to stimulate collaborative research and quality improvements in screening through freely available, comparable and regularly updated quality indicators. The project currently includes data on cervical cancer screening but population-based screening programs for breast cancer and colorectal cancer may be included in the future. Material and methods: Through a network of Nordic and Baltic screening managers, population-based individual screening data from each country were converted to standard format in each collaborative center, aggregated by the same R program script and then uploaded to the NordScreen online platform. Registry data included all cervical tests except for Finland where only tests based on invitation are included. Results: The NordScreen collaboration has so far collated standardized indicators based on 32.8 million screening tests from four Nordic countries and Estonia. Interactive comparison of test coverage and distribution of women by number of tests are currently possible online. In 2016, the test coverage within a time interval of 5.5 years in the age group 30-64 year-olds was between 78 and 84% in Iceland, Norway and Sweden whereas 70% in Finland. The application allows users to choose indicator specifications interactively. Conclusions: NordScreen is a pilot model for comparable, reliable and accessible cross-country comparisons of cancer screening. Comparability between countries is enhanced by a uniform data structure and standardized calculations. The comparison of coverage rates to national figures shows that the methods used nationally and in the NordScreen project produce similar results.

Barriers to cervical cancer screening faced by immigrants: a registry-based study of 1.4 million women in Norway.

Background: Immigrants from certain low- and middle-income countries are more prone to cancers attributed to viral infections in early life. Cervical cancer is caused by human papillomavirus but is highly preventable by regular screening. We assessed participation among immigrants in a population-based cervical screening programme and identified factors that predicted non-adherence within different immigrant groups. Methods: We used data from several nationwide registries. The study population consisted of 208 626 (15%) immigrants and 1 157 223 (85%) native Norwegians. Non-adherence was defined as no eligible screening test in 2008-12. We estimated prevalence ratios with 95% confidence intervals (CIs) for factors associated with non-adherence by modified Poisson regression. Results: In total, 52% of immigrants were not screened. All immigrants showed 1.72 times higher non-adherence rates (95% CI 1.71-1.73) compared with native Norwegian women when adjusted for age and parity. The proportion of non-adherent immigrants varied substantially by region of origin and country of origin. Being unemployed or not in the workforce, being unmarried, having low income and having a male general practitioner was associated with non-adherence regardless of region of origin. Living <10 years in Norway was an evident determinant of non-adherence among most but not all immigrant groups. Conclusions: An increasing proportion of immigrants and low screening participation among them pose new public health challenges in Europe. Immigrants are diverse in terms of their sociodemographic attributes and screening participation. Tailored information and service delivery may be necessary to increase cancer screening among immigrants.

Cytology and human papillomavirus testing 6 to 12 months after ASCUS or LSIL cytology in organized screening to predict high-grade cervical neoplasia between screening rounds.

We carried out a prospective study comparing the performance of human papillomavirus (HPV) E6/E7 mRNA (PreTect HPV-Proofer; NorChip, Klokkarstua, Norway) and DNA (Amplicor HPV test; Roche Diagnostics, Basel, Switzerland) triage testing of women 6 to 12 months after atypical-squamous-cells-of-undetermined-significance (ASCUS) or low-grade-squamous-intraepithelial-lesion (LSIL) cytology in organized screening to predict high-grade cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) between screening rounds. Between January 2005 and April 2008, 692 study women with screening-detected ASCUS/LSIL cytology 6 to 12 months earlier returned for HPV mRNA and DNA testing and repeat cytology. The median follow-up time was 3 years, using existing health care facilities. Follow-up test results were available for 625 women. Of the 145 CIN2+ cases detected during the study period, 95 (65.5%) were HPV mRNA positive 6 to 12 months after screening-detected ASCUS/LSIL, 44 (30.4%) were HPV mRNA negative, and 6 (4.1%) were invalid. The corresponding HPV DNA results were 139 (95.9%), 5 (3.4%), and 1 (0.7%), respectively. The cumulative incidences of CIN2+ 3 years after a negative HPV mRNA and DNA test were 10.3% (95% confidence interval [CI], 7.2 to 13.3%) and 1.8% (95% CI, 0.0 to 3.6%), respectively. The cumulative incidences of CIN2+ 3 years after positive HPV mRNA and DNA tests were 52.8% (95% CI, 40.1 to 60.1%) and 41.3% (95% CI, 35.5 to 46.6%), respectively. In conclusion, both positive HPV mRNA and DNA test results have a high enough long-term prediction of CIN2+ risk to consider referral to colposcopy as good practice when performed in delayed triage of women with ASCUS/LSIL cytology. In addition, the low CIN2+ risk among women with a negative Amplicor HPV test in our study confirms its safe use in a clinical setting.

Impact of the Mobile Game FightHPV on Cervical Cancer Screening Attendance: Retrospective Cohort Study.

BACKGROUND: The wide availability of mobile phones has made it easy to disseminate health-related information and make it accessible. With gamification, mobile apps can nudge people to make informed health choices, including attending cervical cancer screening. OBJECTIVE: This matched retrospective cohort study examined the association between exposure to the FightHPV mobile app gamified educational content and having a cervical exam in the following year. METHODS: Women aged 20 to 69 years who signed an electronic consent form after downloading the FightHPV app in 2017 (intervention group) were matched 1:6 with women of the same age and with the same screening history (reference group) in 2015. To estimate the impact of exposure to the FightHPV app, we estimated cumulative incidence and hazard ratios (HRs) with 95% CIs. We used data from the Norwegian Cervical Cancer Screening Program database and Statistics Norway to determine screening participation and outcomes, respectively. RESULTS: We matched 3860 women in the control group to 658 women in the intervention group; 6 months after enrollment, 29.6% (195/658) of the women in the intervention group and 15.21% (587/3860) of those in the reference group underwent a cervical exam (P<.01). Women exposed to the FightHPV app were 2 times more likely to attend screening (adjusted HR 2.3, 95% CI 2.0-2.7), during which they were 13 times more likely to be diagnosed with high-grade abnormality (adjusted HR 12.7, 95% CI 5.0-32.5) than the women in the reference group. CONCLUSIONS: Exposure to the FightHPV app significantly increased cervical cancer screening attendance across the various analyses and improved detection of women with high risk for cervical cancer. For the first time, we demonstrated the effectiveness of gamification combined with mobile technology in cancer prevention by empowering women to make active health-related decisions. Gamification can significantly improve the understanding of complicated scientific concepts behind interventions and increase the acceptance of proposed cancer control measures.

Randomized Implementation of a Primary Human Papillomavirus Testing-based Cervical Cancer Screening Protocol for Women 34 to 69 Years in Norway.

BACKGROUND: Cervical cancer screening programs are facing a programmatic shift where screening protocol based on human papillomavirus testing (HPV-Screening protocol) is replacing the liquid-based cytology (LBC-Screening protocol). For safe technology transfer within the nationwide screening programme in Norway, HPV-Screening protocol was implemented randomized to compare the real-world effectiveness of HPV-Screening protocol and LBC-Screening protocol at the first screening round. METHODS: Among 302,295 women ages 34 to 69 years scheduled to attend screening from February 2015 to June 2017, 157,447 attended. A total of 77,207 were randomly allocated to the HPV-Screening protocol and 80,240 were allocated to the LBC-Screening protocol. All women were followed up for 18 months. RESULTS: The HPV-Screening protocol resulted in a relative increase of 60% in the detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse [risk ratio (RR) = 1.6, 95% confidence interval (CI) = 1.5-1.7], 40% in CIN grade 3 or worse (RR = 1.4, 95% CI = 1.3-1.6), 40% in cancer (RR = 1.4, 95% CI = 1.0-2.1), and 60% in colposcopy referrals (RR = 1.6, 95% CI = 1.5-1.6) compared with LBC-Screening. The performance of both protocols was age dependent, being more effective in women ages under 50 years. CONCLUSIONS: The HPV-Screening protocol was well accepted by women in Norway and detected more CIN2, CIN3, and cancers compared with the LBC-Screening protocol. IMPACT: A randomized implementation of the HPV-Screening protocol with real-world assessment enabled a gradual, quality assured, and safe technology transition. HPV-based screening protocol may further be improved by using HPV genotyping and age-specific referral algorithms.

Role of high-risk human papillomavirus (HPV) mRNA testing in the prediction of residual disease after conisation for high-grade cervical intraepithelial neoplasia.

OBJECTIVE: To evaluate testing for high-risk human papillomavirus (HR HPV) E6/E7 mRNA transcripts 6 months after conisation for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) to determine the risk of residual CIN2+. METHODS: We prospectively followed 344 women treated for CIN2+ by conisation. HR HPV mRNA testing (PreTect HPV-Proofer, NorChip®), HR HPV DNA testing (AMPLICOR HPV Test, Roche Diagnostics®) and cytology was performed at 6 and 12 months after conisation. Biopsies were taken within 18 months of conisation if indicated by abnormal cytology, abnormal colposcopy, or positive HPV test. The LINEAR ARRAY HPV Genotyping Test (Roche Diagnostics®) was used to genotype cases with histologically confirmed residual disease diagnosed within 18 months after conisation. RESULTS: 6.4% (22/344) of study women had detected residual CIN2+. They were significantly older than those without residual CIN2+ (43.2 and 37.2 years respectively, p<0.001). Among women with detected residual CIN2+, 54.5% (12/22) had positive resection margins, 63.6% (14/22) had abnormal cytology, and 95.5% (21/22) had a positive HR HPV DNA test at 6 months. Sensitivity of HR HPV mRNA testing was 45.5% (95% confidence interval: 26.8-65.5%) at 6 months to predict detected residual CIN2+. Eight of 12 women who were HR HPV mRNA-negative at 6 months were HR HPV DNA-positive for one of the HPV types included in the mRNA test. CONCLUSION: Detection of E6/E7 mRNA transcripts by PreTect HPV Proofer does not seem suitable for short-term follow-up to detect residual CIN2+ after conisation.

Comparison of cytology and human papillomavirus-based primary testing in cervical screening programs in the Nordic countries.

OBJECTIVE: To compare primary test positivity in cytology and human papillomavirus-based screening between different Nordic cervical cancer screening programs using harmonized register data. METHODS: This study utilized individual-level data available in national databases in Finland, Iceland, Norway, and Sweden. Cervical test data from each country were converted to standard format and aggregated by calculating the number of test episodes for every test result for each calendar year and one-year age group and test method. Test positivity was estimated as the proportion of positive test results of all primary test episodes with a valid test result for "any positive" and "clearly positive" results. RESULTS: The age-adjusted rate ratio for any positive test results in primary human papillomavirus-based screening compared to cytology was 1.66 (95% CI 1.64-1.68). The age-adjusted rate ratio for clearly positive test results was 1.02 (95% CI 1.00-1.05). A decreasing rate ratio by age was seen in both any positive and clearly positive test results. Test positivity increased over time in Iceland, Norway, and Sweden but slightly decreased in Finland. CONCLUSIONS: The probability of any positive test result was higher in human papillomavirus testing than in primary cytology, even though the cross-sectional detection of a clearly positive test result was the same. Human papillomavirus testing can still lead to an improved longitudinal sensitivity through a larger number of follow-up tests and the opportunity to identify women with a persistent human papillomavirus infection. Further research on histologically verified precancerous lesions is needed in primary as well as repeat testing.

HPV genotype distribution according to severity of cervical neoplasia.

OBJECTIVE: To analyse the HPV genotype profile and the presence of multiple HPV infections according to severity of cervical intraepithelial neoplasia. METHODS: From a population of 424,143 women in Norway, we included all women (n=643) with histologically confirmed cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and evaluable HPV test during 2005 and 2006. Histology revealed CIN2 in 135 women, CIN3/ACIS in 495, and invasive carcinoma in 13 women. HPV genotyping was performed on cell suspensions from cervix by linear array which differentiates 37 HPV genotypes. RESULTS: HPV was detected in 98.4% (633/643) of the women, of whom 52.5% (338/643) were infected with more than one HPV genotype. HPV16 was most common, being detected in 51.2% (329/643) of all cases, followed by HPV31, 33, 52, 18, and 51. Overall, HPV 16 or 18 were detected in 58.0% (373/643), with 34.7% (223/643) without concurrence of other high-risk genotypes. HPV16 and HPV33 as single infections were more common in women with CIN3+ as compared to CIN2 (age-adjusted odds ratio=5.93, 95% CI=2.73-12.87, and age-adjusted odds ratio=4.53, 95% CI=1.42-14.46, respectively). Concurrent infection with other HPV genotypes did not significantly alter the associations to CIN3+ for HPV16 or HPV33. A single HPV infection, other than HPV16, 18, 31, or 33, was used as the reference. HPV18 or multiple HPV infections not including HPV16 or HPV33 were not associated with the severity of cervical neoplasia. CONCLUSION: HPV16 and HPV33 appear to have a higher oncogenic potential than other HPV genotypes.

Performance of human papillomavirus DNA and mRNA testing strategies for women with and without cervical neoplasia.

In the present study we investigated the cross-sectional positivity for DNA and E6/E7 mRNA from high-risk human papillomavirus (HPV) types in 643 women with high-grade cervical neoplasia (135 cases of cervical intraepithelial neoplasia grade 2 [CIN2], 495 cases of CIN3/adenocarcinoma in situ [ACIS], and 13 cases of invasive carcinoma) and in 736 women with normal cytology by using the Amplicor and PreTect HPV-Proofer assays. In addition, genotyping was performed using Linear Array for women with normal cytology and a positive HPV test and in all women with histologically confirmed CIN2+. In women with normal cytology, 8.3% (61/736) were Amplicor positive and 3.3% (24/736) were PreTect HPV-Proofer positive (P < 0.001). Concordant results between the Amplicor and PreTect HPV-Proofer tests were present in 90.3% (665/736). In women with CIN2+ lesions 96.4% (620/643) were positive by Amplicor, 98.4% (633/643) by linear array, and 64.1% (412/643) by PreTect HPV-Proofer. Concordant results for the three HPV assays were present in 63.8%. The genotype profile detected by linear array and PreTect HPV-Proofer showed substantial agreement for HPV types 16, 18, 33, and 45. HPV type 16 and/or 18 was detected in 58.8% (378/643) of the women with high-grade neoplasia. Detection of E6/E7 mRNA by PreTect HPV-Proofer increased with severity of the cervical lesion. Detection of HPV DNA, however, was not associated with histology grade. In conclusion, the detection of HPV varied according to the assay used, and the concordance between the tests was poor. Our results indicate that mRNA testing may be a biomarker for progression of cervical neoplasia, but the optimal genotype mix remains to be determined.