K. Miriam Elfström

Long term duration of protective effect for HPV negative women: follow-up of primary HPV screening randomised controlled trial

Objectives To assess whether the increased sensitivity of screening for human papillomavirus (HPV) may represent overdiagnosis and to compare the long term duration of protective effect against cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in HPV based and cytology based screening. Design 13 year follow-up of the Swedescreen randomised controlled trial of primary HPV screening. Setting Organised cervical screening programme in Sweden. Participants 12 527 women aged 32-38 attending organised screening were enrolled and randomised to HPV and cytology double testing (intervention arm, n=6257) or to cytology only, with samples frozen for future HPV testing (control arm, n=6270). Main outcome measures Cumulative incidence of CIN2+ and CIN3+ (Kaplan Meier curves). Longitudinal test characteristics were calculated for cytology only, HPV testing only, and cytology and HPV testing combined, adjusting for censoring. Results The increased detection of CIN2+ in the intervention arm decreased over time. After six years, the cumulative incidence of CIN3+ was similar in both trial arms, and after 11 years the cumulative incidence of CIN2+ became similar in both arms. The longitudinal sensitivity of cytology for CIN2+ in the control arm at three years was similar to the sensitivity of HPV testing in the intervention arm at five years of follow-up: 85.94% (95% confidence interval 76.85% to 91.84%) v 86.40% (79.21% to 91.37%). The sensitivity of HPV screening for CIN3+after five years was 89.34% (80.10% to 94.58%) and for cytology after three years was 92.02% (80.59% to 96.97%). Conclusions Over long term follow-up, the cumulative incidence of CIN2+ was the same for HPV screening and for cytology, implying that the increased sensitivity of HPV screening for CIN2+ reflects earlier detection rather than overdiagnosis. The low long term risks of CIN3+ among women who tested negative in HPV screening, support screening intervals of five years for such women. Trial registration Clinicaltrials.gov NCT00479375.

Cervical cancer screening in Europe: Quality assurance and organisation of programmes.

BACKGROUND Cervical screening programmes have reduced cervical cancer incidence and mortality but the level of success is highly variable between countries. Organisation of programmes is essential for equity and cost-effectiveness. However, there are differences in effectiveness, also among organised programmes. In order to identify the key organisational components that determine effectiveness, we performed a Europe-wide survey on the current status of organisation and organised quality assurance (QA) measures in cervical cancer prevention programmes, as well as organisation-associated costs. METHODS A comprehensive questionnaire was developed through systematic review of literature and existing guidelines. The survey was sent to programme organisers, Ministries of Health and experts in 34 European Union (EU) and European Free Trade Agreement (EFTA) countries. Detailed aspects of programme organisation, quality assurance, monitoring, evaluation and corresponding line-item costs were recorded. Documentation of programme guidelines, protocols and publications was requested. RESULTS Twenty-nine of 34 countries responded. The results showed that organised efforts for QA, monitoring and evaluation were carried out to a differing extent and were not standardised, making it difficult to compare the cost-effectiveness of organisation and QA strategies. Most countries found it hard to estimate the costs associated with launching and operating the organised programme. CONCLUSIONS To our knowledge, this is the first questionnaire to request detailed information on the actual organisation and QA of programmes. The results of this survey can be used as a basis for further development of standardised guidelines on organisation and QA of cervical cancer screening programmes in Europe.

Long‐term HPV type‐specific risks of high‐grade cervical intraepithelial lesions: A 14‐year follow‐up of a randomized primary HPV screening trial

Quantitative knowledge of the long‐term human papillomavirus (HPV) type‐specific risks for high‐grade cervical intraepithelial neoplasias Grades 2 and 3 (CIN2 and CIN3) is useful for estimating the effect of elimination of specific HPV types and clinical benefits of screening for specific HPV types. We estimated HPV type‐specific risks for CIN2 and CIN3 using a randomized primary HPV screening trial followed up for 14.6 years using comprehensive, nationwide registers. Poisson regression estimated cumulative incidences, population attributable proportions (PAR) and incidence rate ratios (IRRs) of high‐grade lesions by baseline HPV type, with censoring at date of first CIN2/3 or last registered cytology. Multivariate analysis adjusted for coinfections. IRRs were highest during the first screening round, but continued to be high throughout follow‐up (IRRs for CIN3 associated with high‐risk (HR) HPV positivity were 226.9, 49.3, 17.7 and 10.3 during the first, second and third screening round and for >9 years of follow‐up, respectively). Increased long‐term risks were found particularly for HPV Types 16, 18 and 31 and for CIN3+ risks. HPV16/18/31/33 had 14‐year cumulative incidences for CIN3+ above 28%, HPV35/45/52/58 had 14 year risks between 14% and 18% and HPV39/51/56/59/66/68 had risks <10%. HPV16 contributed to the greatest proportion of CIN2+ (first round PAR 36%), followed by Types 31, 52, 45 and 58 (7–11%). HPV16/18/31/33/45/52/58 together contributed 73.9% of CIN2+ lesions and all HR types contributed 86.9%. In summary, we found substantial differences in risks for CIN2 and CIN3 between different oncogenic HPV types. These differences may be relevant for both clinical management and design of preventive strategies.

Human Papillomavirus Vaccination of Boys and Extended Catch-up Vaccination: Effects on the Resilience of Programs

BACKGROUND Decreasing human papillomavirus (HPV) vaccine prices makes scaling up of vaccination programs attractive for countries that initially targeted 1 or a few birth cohorts of girls and/or achieved low coverage. This article aims to compare the impact of alternative HPV vaccination strategies, using data from Sweden, a high-income country that has experienced vaccine price changes. METHODS Using an HPV transmission model, we compared the existing vaccination program to alternatives, accounting for a 1-time catch-up vaccination of 22-26-year-old women, with or without routine vaccination of school-age boys, and for a 1-time catch-up vaccination of males aged 13-26 years. We also assessed the resilience of vaccination alternatives to coverage reduction. RESULTS On the basis of an HPV16/18 prevalence of 12% before the HPV vaccine era, extended catch-up vaccination for females and males yielded relative reductions in the HPV prevalence of 49.4% and 55.6%, respectively, during the first 10 years after the start of each vaccination strategy, whereas the existing program yielded a relative reduction of 38.6% during the same period. The increased prevalence reduction due to catch-up vaccination continued for about 30 years. As compared to female-only routine and extended catch-up vaccination, routine vaccination of males with or without catch-up was, respectively, 12.6-fold and 7.2-fold more resilient to coverage reduction. CONCLUSIONS Vaccination strategies based on catch-up vaccination of females and males are effective for accelerating HPV prevalence reduction. Inclusion of routine male vaccination improves the resilience of vaccination programs.

Organization and quality of HPV vaccination programs in Europe.

BACKGROUND HPV vaccination is underway in most European countries, but there are limited efforts toward optimization and standardization of organization, monitoring and evaluation. Our Europe-wide survey sought to identify how programs are currently organized, the costs associated with the organizing and ensuring quality of the program and how quality and effectiveness measurements are carried out. METHODS A comprehensive questionnaire was developed through systematic literature review and the European guidelines for quality assurance in cervical screening. The survey was piloted in a sub-set of countries and then sent to program organizers, Ministries of Health, and key experts in 34 EU and EFTA countries (including countries within the UK). Detailed information on program organization and target population, monitoring and evaluation (including indicators used for evaluating the impact of vaccination), and associated costs were collected. In addition, documentation of program guidelines, protocols, and publications were requested. RESULTS Of the 34 countries contacted, 27 responded. The majority of countries had some level of vaccination activity, with approximately half of the countries reporting an organized vaccination program. Centralized vaccine registries were in place in the majority of countries with an organized program, allowing for monitoring of key indicators at the national level. Costs of organization and monitoring were difficult to estimate and varied significantly, as some countries were able to use existing infrastructures while others had to create new systems, incurring greater costs. CONCLUSIONS The organization and quality of HPV vaccination programs differ across countries and, in some instances, even across regions within the same country. The monitoring being performed varies across programs with regard to level of detail but engagement in the survey from the participating countries demonstrates that there is strong interest in reflecting on and improving program performance. This survey could serve as a basis for strengthening surveillance of HPV vaccination programs.

Triage of HR-HPV Positive Women with Minor Cytological Abnormalities: A Comparison of mRNA Testing, HPV DNA Testing, and Repeat Cytology Using a 4-Year Follow-Up of a Population-Based Study

Objective Expression of the viral E6/E7 oncogenes of high-risk human papillomaviruses (HR-HPV) is necessary for malignant conversion and maintenance in cervical tissue. In order to determine whether HR-HPV E6/E7 mRNA testing more effectively predicts precancerous lesions and invasive cervical cancer than HR-HPV DNA testing, we aimed to compare triage using HR-HPV E6/E7 mRNA testing by APTIMA HPV Assay (APTIMA) to HPV16 DNA testing, HPV16/18 DNA testing, and repeat cytology. Methods Liquid-based (PreservCyt) cell samples were obtained from HR-HPV-positive women diagnosed with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) within the framework of the population-based cervical cancer screening program in Stockholm, Sweden. Samples were tested for HR-HPV E6/E7 mRNA by APTIMA (Gene-Probe Inc., San Diego, CA, USA). Women were followed up for 4 years after the index cytology via medical and laboratory records, and the Stockholm Oncology Center. Results Nine of 25 (36%) women in the ASCUS group, and 64 of 180 (36%) women in the LSIL group developed cervical intraepithelial neoplasia (CIN) grade 2 or worse during 4 years of follow-up. 162 (74%) women were APTIMA-positive, and APTIMA had the highest sensitivity to predict CIN2 or worse and CIN3 or worse in the ASCUS (77.8% and 100%) and LSIL (78.1 and 75.8%) groups, although specificity was insufficient (<50%). HPV16 DNA testing and repeat cytology were more specific than APTIMA. Conclusion The results of this population-based study with comprehensive follow-up support the use of APTIMA as a triage test for women with ASCUS. More focused investigation is required for women with LSIL.

Type-specific human papillomavirus biological features: validated model-based estimates.

Infection with high-risk (hr) human papillomavirus (HPV) is considered the necessary cause of cervical cancer. Vaccination against HPV16 and 18 types, which are responsible of about 75% of cervical cancer worldwide, is expected to have a major global impact on cervical cancer occurrence. Valid estimates of the parameters that regulate the natural history of hrHPV infections are crucial to draw reliable projections of the impact of vaccination. We devised a mathematical model to estimate the probability of infection transmission, the rate of clearance, and the patterns of immune response following the clearance of infection of 13 hrHPV types. To test the validity of our estimates, we fitted the same transmission model to two large independent datasets from Italy and Sweden and assessed finding consistency. The two populations, both unvaccinated, differed substantially by sexual behaviour, age distribution, and study setting (screening for cervical cancer or Chlamydia trachomatis infection). Estimated transmission probability of hrHPV types (80% for HPV16, 73%-82% for HPV18, and above 50% for most other types); clearance rates decreasing as a function of time since infection; and partial protection against re-infection with the same hrHPV type (approximately 20% for HPV16 and 50% for the other types) were similar in the two countries. The model could accurately predict the HPV16 prevalence observed in Italy among women who were not infected three years before. In conclusion, our models inform on biological parameters that cannot at the moment be measured directly from any empirical data but are essential to forecast the impact of HPV vaccination programmes.

Inference of Type-Specific HPV Transmissibility, Progression and Clearance Rates: A Mathematical Modelling Approach.

Quantifying rates governing the clearance of Human Papillomavirus (HPV) and its progression to clinical disease, together with viral transmissibility and the duration of naturally-acquired immunity, is essential in estimating the impact of vaccination programmes and screening or testing regimes. However, the complex natural history of HPV makes this difficult. We infer the viral transmissibility, rate of waning natural immunity and rates of progression and clearance of infection of 13 high-risk and 2 non-oncogenic HPV types, making use of a number of rich datasets from Sweden. Estimates of viral transmissibility, clearance of initial infection and waning immunity were derived in a Bayesian framework by fitting a susceptible-infectious-recovered-susceptible (SIRS) transmission model to age- and type-specific HPV prevalence data from both a cross-sectional study and a randomised controlled trial (RCT) of primary HPV screening. The models fitted well, but over-estimated the prevalence of four high-risk types with respect to the data. Three of these types (HPV-33, -35 and -58) are among the most closely related phylogenetically to the most prevalent HPV-16. The fourth (HPV-45) is the most closely related to HPV-18; the second most prevalent type. We suggest that this may be an indicator of cross-immunity. Rates of progression and clearance of clinical lesions were additionally estimated from longitudinal data gathered as part of the same RCT. Our estimates of progression and clearance rates are consistent with the findings of survival analysis studies and we extend the literature by estimating progression and clearance rates for non-16 and non-18 high-risk types. We anticipate that such type-specific estimates will be useful in the parameterisation of further models and in developing our understanding of HPV natural history.

Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial

Background: Introduction of human papillomavirus–based screening is ongoing in many countries, given its higher sensitivity and longer‐lasting protection compared with cytology‐based screening. However, optimal clinical management of human papillomavirus–positive but cytology‐negative women is unclear, and additional studies with clinical follow‐up are warranted. Objective: The aim of the current study was to investigate the long‐term outcomes of the clinical management used in a double‐blind, randomized clinical trial of human papillomavirus screening conducted in the context of the routine, organized screening program in Sweden. Study Design: Among 12,527 women aged 32–38 years enrolled in the trial, we followed up the 195 women who attended the colposcopy screening who were cytologically normal but persistently human papillomavirus positive (at least 12 months later; median, 19 months) in the human papillomavirus testing arm (n = 100) or were randomly selected from the control arm (n = 95). Women in the human papillomavirus testing arm were followed up with repeated human papillomavirus testing, cytologies, and colposcopies if persistently human papillomavirus–positive without cervical intraepithelial neoplasia grade 2 or worse. A similar number of random colposcopies and tests were carried out in the control arm. Women were followed up over 13 years for the main outcome measures: cumulative incidence of cervical intraepithelial neoplasia grade 2 or worse and cervical intraepithelial neoplasia grade 3 or worse. Results: Among women who continued to attend and had continuous human papillomavirus persistence, all (40 of 40, 100% [95% confidence interval, 91–100%]) developed cervical intraepithelial neoplasia grade 2 or worse. There were no cases among women who cleared their human papillomavirus persistence (0 of 35, 0% (95% confidence interval, 0–10%) (P < .001). Among women who had had human papillomavirus persistence but did not continue with repeated human papillomavirus tests (unknown persistence status), 56% (15 of 27 women) developed cervical intraepithelial neoplasia grade 2 or worse. Almost all cases occurred within 6 years. The intensive clinical management in the trial appeared to result in diagnoses of earlier cervical intraepithelial neoplasia grade 2 or worse but apparently did not prevent cervical intraepithelial neoplasia grade 2 or worse. Conclusion: Women with human papillomavirus persistence will, in general, either become human papillomavirus negative or develop cervical intraepithelial neoplasia grade 2 or worse within 6 years, even with intensive clinical follow‐up.

Risk of invasive cervical cancer after atypical glandular cells in cervical screening: nationwide cohort study

Objectives To investigate the risks of invasive cervical cancer after detection of atypical glandular cells (AGC) during cervical screening. Design Nationwide population based cohort study. Setting Cancer and population registries in Sweden. Participants 3 054 328 women living in Sweden at any time between 1 January 1980 and 1 July 2011 who had any record of cervical cytological testing at ages 23-59. Of these, 2 899 968 women had normal cytology results at the first screening record. The first recorded abnormal result was atypical glandular cells (AGC) in 14 625, high grade squamous intraepithelial lesion (HSIL) in 65 633, and low grade squamous intraepithelial lesions (LSIL) in 244 168. Main outcome measures Cumulative incidence of invasive cervical cancer over 15.5 years; proportion of invasive cervical cancer within six months of abnormality (prevalence); crude incidence rates for invasive cervical cancer over 0.5-15.5 years of follow-up; incidence rate ratios compared with women with normal cytology, estimated with Poisson regression adjusted for age and stratified by histopathology of cancer; distribution of clinical assessment within six months after the abnormality. Results The prevalence of cervical cancer was 1.4% for women with AGC, which was lower than for women with HSIL (2.5%) but higher than for women with LSIL (0.2%); adenocarcinoma accounted for 73.2% of the prevalent cases associated with AGC. The incidence rate of invasive cervical cancer after AGC was significantly higher than for women with normal results on cytology for up to 15.5 years and higher than HSIL and LSIL for up to 6.5 years. The incidence rate of adenocarcinoma was 61 times higher than for women with normal results on cytology in the first screening round after AGC, and remained nine times higher for up to 15.5 years. Incidence and prevalence of invasive cervical cancer was highest when AGC was found at ages 30-39. Only 54% of women with AGC underwent histology assessment within six months, much less than after HSIL (86%). Among women with histology assessment within six months, the incidence rate of cervical cancer after AGC was significantly higher than that after HSIL for up to 6.5 years. Conclusions AGC found at cervical screening is associated with a high and persistent risk of cervical cancer for up to 15 years, particularly for cervical adenocarcinoma and women with AGC at age 30-39. Compared with the reduction in risk of cancer seen after HSIL management, management of AGC seems to have been suboptimal in preventing cervical cancer. Research to optimise management is needed, and a more aggressive assessment strategy is warranted.