Lisen Arnheim-Dahlström

Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study

Objective To assess the risk of serious adverse events after vaccination of adolescent girls with quadrivalent human papillomavirus (qHPV) vaccine. Design Register based cohort study. Setting Denmark and Sweden, October 2006 to December 2010. Participants 997 585 girls aged 10-17, among whom 296 826 received a total of 696 420 qHPV vaccine doses. Main outcome measures Incident hospital diagnosed autoimmune, neurological, and venous thromboembolic events (53 different outcomes) up to 180 days after each qHPV vaccine dose. Only events with at least five vaccine exposed cases were considered for further assessment. Rate ratios adjusted for age, country, calendar year, and parental country of birth, education, and socioeconomic status were estimated, comparing vaccinated and unvaccinated person time. For outcomes where the rate ratio was significantly increased, we regarded three criteria as signal strengthening: analysis based on 20 or more vaccine exposed cases (reliability), rate ratio 3.0 or more (strength), and significantly increased rate ratio in country specific analyses (consistency). We additionally assessed clustering of events in time and estimated rate ratios for a risk period that started on day 181. Results Among the 53 outcomes, at least five vaccine exposed cases occurred in 29 and these were analysed further. Whereas the rate ratios for 20 of 23 autoimmune events were not significantly increased, exposure to qHPV vaccine was significantly associated with Behcet’s syndrome, Raynaud’s disease, and type 1 diabetes. Each of these three outcomes fulfilled only one of three predefined signal strengthening criteria. Furthermore, the pattern of distribution in time after vaccination was random for all three and the rate ratios for these outcomes in the period from day 181 after vaccination were similar to the rate ratios in the primary risk period. The rate ratios for five neurological events were not significantly increased and there were inverse associations with epilepsy (rate ratio 0.66, 95% confidence interval 0.54 to 0.80) and paralysis (0.56, 0.35 to 0.90). There was no association between exposure to qHPV vaccine and venous thromboembolism (0.86, 0.55 to 1.36). Conclusions This large cohort study found no evidence supporting associations between exposure to qHPV vaccine and autoimmune, neurological, and venous thromboembolic adverse events. Although associations for three autoimmune events were initially observed, on further assessment these were weak and not temporally related to vaccine exposure. Furthermore, the findings need to be interpreted considering the multiple outcomes assessed.

Quadrivalent Human Papillomavirus Vaccine Effectiveness: A Swedish National Cohort Study

Background Incidence of condyloma, or genital warts (GW), is the earliest possible disease outcome to measure when assessing the effectiveness of human papillomavirus (HPV) vaccination strategies. Efficacy trials that follow prespecified inclusion and exclusion criteria may not be fully generalizable to real-life HPV vaccination programs, which target a broader segment of the population. We assessed GW incidence after on-demand vaccination with quadrivalent HPV vaccine using individual-level data from the entire Swedish population. Methods An open cohort of girls and women aged 10 to 44 years living in Sweden between 2006 and 2010 (N > 2.2 million) was linked to multiple population registers to identify incident GW in relation to HPV vaccination. For vaccine effectiveness, incidence rate ratios of GW were estimated using time-to-event analyses with adjustment for attained age and parental education level, stratifying on age at first vaccination. Results A total of 124 000 girls and women were vaccinated between 2006 and 2010. Girls and women with at least one university-educated parent were 15 times more likely to be vaccinated before age 20 years than girls and women whose parents did not complete high school (relative risk ratio = 15.45, 95% confidence interval [CI] = 14.65 to 16.30). Among those aged older than 20 years, GW rates declined among the unvaccinated, suggesting that HPV vaccines were preferentially used by women at high risk of GW. Vaccination effectiveness was 76% (95% CI = 73% to 79%) among those who received three doses of the vaccine with their first dose before age 20 years. Vaccine effectiveness was highest in girls vaccinated before age 14 years (effectiveness = 93%, 95% CI = 73% to 98%). Conclusions Young age at first vaccination is imperative for maximizing quadrivalent HPV vaccine effectiveness.

Quadrivalent HPV Vaccination and Risk of Multiple Sclerosis and Other Demyelinating Diseases of the Central Nervous System

IMPORTANCE Case reports have suggested a link between human papillomavirus (HPV) vaccination and development of multiple sclerosis and other demyelinating diseases. OBJECTIVE To investigate if quadrivalent HPV (qHPV) vaccination is associated with an increased risk of multiple sclerosis and other demyelinating diseases. DESIGN, SETTING, AND PARTICIPANTS Using nationwide registers we identified a cohort of all females aged 10 years to 44 years in Denmark and Sweden, followed up from 2006 to 2013, information on qHPV vaccination, and data on incident diagnoses of multiple sclerosis and other demyelinating diseases. The primary analysis used a cohort design including vaccinated and unvaccinated study participants. A secondary analysis used a self-controlled case-series design including only cases. Both analyses used a 2-year risk period following vaccination. EXPOSURES Information on qHPV vaccination was obtained through the national vaccination and prescription registers. MAIN OUTCOMES AND MEASURES The primary outcomes were multiple sclerosis and a composite end point of other demyelinating diseases. Incidence rate ratios were estimated using Poisson regression, comparing rates of events in the 2-year risk periods following vaccination and in unvaccinated time periods. RESULTS The study included 3,983,824 females, among whom 789,082 received a total of 1,927,581 qHPV vaccine doses. During follow-up, 4322 multiple sclerosis cases and 3300 cases of other demyelinating diseases were identified, of which 73 and 90, respectively, occurred within the risk period. In the cohort analysis, there was no increased risk of multiple sclerosis (crude incidence rates, 6.12 events/100,000 person-years [95% CI, 4.86-7.69] and 21.54 events/100,000 person-years [95% CI, 20.90-22.20] for the vaccinated and unvaccinated periods; adjusted rate ratio, 0.90 [95% CI, 0.70-1.15]) or other demyelinating diseases (crude incidence rates, 7.54 events/100,000 person-years [95% CI, 6.13-9.27] and 16.14 events/100,000 person-years [95% CI, 15.58-16.71]; adjusted rate ratio, 1.00 [95% CI, 0.80-1.26]) associated with qHPV vaccination. Similarly, no increased risk was found using the self-controlled case-series design (multiple sclerosis: incidence ratio, 1.05 [95% CI, 0.79-1.38]; other demyelinating diseases: incidence ratio, 1.14 [95% CI, 0.88-1.47]). CONCLUSIONS AND RELEVANCE In this study with nationwide coverage of 2 Scandinavian countries, qHPV vaccination was not associated with the development of multiple sclerosis or other demyelinating diseases. These findings do not support concerns about a causal relationship between qHPV vaccination and demyelinating diseases.

Incidence of Genital Warts in Sweden Before and After Quadrivalent Human Papillomavirus Vaccine Availability

BACKGROUND More than 90% of genital warts (GW) cases are caused by human papillomavirus (HPV) types 6 and 11. The introduction of HPV vaccines necessitates the estimation of the population-based incidence of GW immediately before and after vaccination uptake. METHODS Incidence proportions were calculated using the entire population aged 10–44 years living in Sweden during 2006–2010. The Prescribed Drug Register and the National Patient Register were used to define GW episodes. Time trends were estimated using Poisson regression. RESULTS In 2010, age-stratified incidence proportions of GW were highest for 20-year-old women (956 cases/100 000), while the incidence proportion among males was greatest at the slightly older age of 24 years (1137 cases/100 000). Crude rates were marginally higher among males than among females during 2006–2007 and appeared to later diverge. Between 2008 and 2010, the overall incidence appeared to increase among males, and the incidence among females declined. Females aged 17 and 18 years had a >25% decline in GW rates between 2006 and 2010, with significant decreases through the age of 25 years. CONCLUSIONS This study provides a reasonable estimation of the incidence of GW in the Swedish population by use of register data, with results comparable to those from previous smaller studies. There was a downward trend of GW incidence among younger females between 2006 and 2010.

Association of Varying Number of Doses of Quadrivalent Human Papillomavirus Vaccine With Incidence of Condyloma

IMPORTANCE Determining vaccine dose-level protection is essential to minimize program costs and increase mass vaccination program feasibility. Currently, a 3-dose vaccination schedule is recommended for both the quadrivalent and bivalent human papillomavirus (HPV) vaccines. Although the primary goal of HPV vaccination programs is to prevent cervical cancer, condyloma related to HPV types 6 and 11 is also prevented with the quadrivalent vaccine and represents the earliest measurable preventable disease outcome for the HPV vaccine. OBJECTIVE To examine the association between quadrivalent HPV vaccination and first occurrence of condyloma in relation to vaccine dose in a population-based setting. DESIGN, SETTING, AND PARTICIPANTS An open cohort of all females aged 10 to 24 years living in Sweden (n = 1,045,165) was followed up between 2006 and 2010 for HPV vaccination and first occurrence of condyloma using the Swedish nationwide population-based health data registers. MAIN OUTCOMES AND MEASURES Incidence rate ratios (IRRs) and incidence rate differences (IRDs) of condyloma were estimated using Poisson regression with vaccine dose as a time-dependent exposure, adjusting for attained age and parental education, and stratified on age at first vaccination. To account for prevalent infections, models included a buffer period of delayed case counting. RESULTS A total of 20,383 incident cases of condyloma were identified during follow-up, including 322 cases after receipt of at least 1 dose of the vaccine. For individuals aged 10 to 16 years at first vaccination, receipt of 3 doses was associated with an IRR of 0.18 (95% CI, 0.15-0.22) for condyloma, whereas receipt of 2 doses was associated with an IRR of 0.29 (95% CI, 0.21-0.40). One dose was associated with an IRR of 0.31 (95% CI, 0.20-0.49), which corresponds to an IRD of 384 cases (95% CI, 305-464) per 100,000 person-years, compared with no vaccination. The corresponding IRDs for 2 doses were 400 cases (95% CI, 346-454) and for 3 doses, 459 cases (95% CI, 437-482). The number of prevented cases between 3 and 2 doses was 59 (95% CI, 2-117) per 100,000 person-years. CONCLUSIONS AND RELEVANCE Although maximum reduction in condyloma risk was seen after receipt of 3 doses of quadrivalent HPV vaccine, receipt of 2 vaccine doses was also associated with a considerable reduction in condyloma risk. The implications of these findings for the relationship between number of vaccine doses and cervical cancer risk require further investigation.

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.

Quadrivalent HPV vaccine effectiveness against high-grade cervical lesions by age at vaccination: A population-based study.

Human papillomavirus (HPV) types 16/18, included in HPV vaccines, contribute to the majority of cervical cancer, and a substantial proportion of cervical intraepithelial neoplasia (CIN) grades 2/3 or worse (CIN2+/CIN3+) including adenocarcinoma in situ or worse. The aim of this study was to quantify the effect of quadrivalent HPV (qHPV) vaccination on incidence of CIN2+ and CIN3+. A nationwide cohort of girls and young women resident in Sweden 2006–2013 and aged 13–29 (n = 1,333,691) was followed for vaccination and histologically confirmed high‐grade cervical lesions. Data were collected using the Swedish nationwide healthcare registers. Poisson regression was used to calculate incidence rate ratios (IRRs) and vaccine effectiveness [(1‐IRR)x100%] comparing fully vaccinated with unvaccinated individuals. IRRs were adjusted for attained age and parental education, and stratified on vaccination initiation age. Effectiveness against CIN2+ was 75% (IRR = 0.25, 95%CI = 0.18–0.35) for those initiating vaccination before age 17, and 46% (IRR = 0.54, 95%CI = 0.46–0.64) and 22% (IRR = 0.78, 95%CI = 0.65–0.93) for those initiating vaccination at ages 17–19, and at ages 20–29, respectively. Vaccine effectiveness against CIN3+ was similar to vaccine effectiveness against CIN2+. Results were robust for both women participating to the organized screening program and for women at prescreening ages. We show high effectiveness of qHPV vaccination on CIN2+ and CIN3+ lesions, with greater effectiveness observed in girls younger at vaccination initiation. Continued monitoring of impact of HPV vaccination in the population is needed in order to evaluate both long‐term vaccine effectiveness and to evaluate whether the vaccination program achieves anticipated effects in prevention of invasive cervical cancer.

Human papillomavirus (HPV) vaccination and subsequent sexual behaviour: Evidence from a large survey of Nordic women ☆

OBJECTIVE To assess whether recipients and non-recipients of the human papillomavirus (HPV) vaccine subsequently differ in terms of sexual risk taking behaviour. DESIGN Cross-sectional survey. Sequential analyses constructed from self-reported age at vaccination, age at first intercourse and age at response. SETTING A random selection of women aged 18-46 years living in Denmark, Norway and Sweden in 2011-2012, eligible for opportunistic or organized catch-up HPV vaccination. PARTICIPANTS A total of 3805 women reported to have received the HPV vaccine and 40,247 reported not to have received it. Among vaccinees, 1539 received the HPV vaccine before or at the same age as sexual debut, of which 476 and 1063 were eligible for organized catch-up and opportunistic vaccination, respectively. MAIN OUTCOME MEASURES Self-reported sexual behaviour, compared by hazard ratios and odds ratios for women who received the HPV vaccine before or at the same age as sexual debut versus women who did not receive the HPV vaccine. RESULTS HPV vaccination did not result in younger age at first intercourse. Women who received the HPV vaccine before or at the same age as sexual debut did not have more sexual partners than did non-vaccinees. Non-use of contraception during first intercourse was more common among non-vaccinees than among HPV vaccinees. The results were similar for organized catch-up and opportunistic vaccinees. CONCLUSION Women who received the HPV vaccine before or at the same age as sexual debut did not subsequently engage more in sexual risk taking behaviour than women who did not receive the HPV vaccine.

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.