Jeppe Bennekou Schroll

Human papillomavirus prevalence in first, second and third cervical cell samples from women HPV-vaccinated as girls, Denmark, 2017 to 2024: data from the Trial23 cohort study

BACKGROUND Danish women vaccinated with the 4-valent human papillomavirus (HPV) vaccine (HPV types: 6/11/16/18) at age 14 in 2008 reached screening age in 2017, allowing assessment of long-term effects on prevalence, persistence and incidence of HPV infections. AIM To examine the HPV status of cervical samples over time among women vaccinated as girls. METHODS Between February 2017 and February 2024, residual material from cytology-analysed samples collected through the ‘Trial23’ study, part of the national screening programme, was tested for HPV16/18 and non-vaccine high-risk (HR) HPV types. Prevalence in first, second and third samples, and persistence and incidence between samples were calculated. RESULTS Over 7 years, 8,659 women provided at least one sample, 5,835 at least two and 2,461 at least three. In 7,800 vaccinated women, HPV16/18 prevalence was 0.4% (95% confidence interval (CI): 0.2–0.5), 0.3% (95% CI: 0.1–0.4) and 0.2% (95% CI: 0.0–0.4) in three consecutive samples. Prevalence of non-vaccine HR HPV was 32% (95% CI: 31–33), 28% (95% CI: 27–29) and 31% (95% CI: 29–33). Persistence of HPV16/18 and non-vaccine HPV among vaccinated women was 40% and 53%. In adjusted analyses comparing vaccinated vs unvaccinated women, incidence was significantly lower for HPV16/18 (adjusted relative risk (aRR) < 0.10) while incidence of non-vaccine HR HPV types was higher (aRR: 1.66; 95% CI: 1.12–2.45). No significant difference was observed for persistence. CONCLUSION Our study provides real-world evidence of stable protection against HPV16/18 infections in women vaccinated as girls. Less intensive screening seems reasonable until women vaccinated with the 9-valent vaccine reach screening age, when screening should be reconsidered.

Outcomes associated with large loop excision of the cervical transformation zone in women 60–64 years of age: A population‐based register study from Denmark

AbstractIntroductionFor women treated for cervical dysplasia at 60–64 years in Denmark, we reported the frequency of abnormalities before and after treatment of cervix uteri (most frequently performed as large loop excision of the cervical transformation zone, LLETZ) using population‐based real‐world data.Material and MethodsWe conducted a retrospective cohort study based on national data from the Danish Pathology Data Bank and identified women who underwent a LLETZ in 2010–2016 at the age of 60–64. Women were managed according to nationwide evidence‐based recommendations proposed by the Danish professional organizations. We retrieved information on all LLETZ specimens, cervical histology, cytology, and human papillomavirus (HPV) tests in the period of 2 years prior to the procedure to 2 years thereafter. We reported the frequencies of abnormalities before, at, or after the procedure.ResultsOf the 1014 women who had a LLETZ during the study period, 660 (65%) showed cervical intraepithelial neoplasia grade 1 or worse (CIN1+, including CIN1, CIN2, CIN3, cervical cancer, and CIN not otherwise specified) in their LLETZ specimen, with free resection margins in 255 (39%). Of the 1014 women, 551 (54%) had CIN2+ in a biopsy preceding the LLETZ and in 567 (56%) CIN2+ was found in their LLETZ specimen. In 37 (4%) women, the specimen showed cervical cancer; whereas in the pre‐LLETZ biopsies of these 37 women, cancer was detected in only 7 (1%). After LLETZ, 818 (81%) women underwent test‐of‐cure follow‐up which was positive in 406 women (40%). Furthermore, 408 (40%) women had new histological samples registered after LLETZ. These showed CIN2+ in 134 (13%) women, whereas a new cancer was diagnosed in 11 (1%) women.ConclusionsDue to persistent abnormal tests after LLETZ, an extended follow‐up is still required for a large proportion of the women in this age group.

Cervical cancer incidence in Denmark: Disentangling determinants of time trend

AbstractCervical cancer is a preventable disease. Nevertheless, stagnation has been seen in incidence rates also in countries with well‐functioning healthcare. On this basis, we investigated associations between control interventions and changes in cervical cancer incidence in Denmark from 2009 to 2022. Data on human papillomavirus (HPV)‐vaccination were retrieved from Staten's Serum Institute; on screening recommendations from Danish Health Authority, on screening performance from Danish Quality Database for Cervical Screening; and on cervical cancer incidence from Nordcan and Danish Cancer Register. We reported coverage with HPV vaccination (1+ dose); coverage with cervical cell samples; number of women with primary HPV tests; proportion of non‐normal cell samples without timely follow‐up; number of conizations; and cervical cancer incidence rates. In 2022, all women aged ≤29 had been offered childhood HPV vaccination with coverage of 80%–90%. By 2020–2022, the cervical cancer incidence rate in women aged 20–29 was 3 per 100,000; at level of disease elimination. In 2017, women aged 70+ were offered a one‐time HPV screening, and by 2020–2022, the old‐age peak in cervical cancer incidence had largely disappeared. From 2009 to 2022, proportion of non‐normal cell samples without timely follow‐up decreased from 20% to 10%, and conventional cytology was largely replaced by SurePath liquid‐based cytology; these factors could explain the steady decrease in cervical cancer incidence rate. Implementation of primary HPV screening in women aged 30–59 in 2021 was reflected in a, probably temporary, increase in the 2022 cervical cancer incidence rate. In conclusion, combined interventions with childhood HPV vaccination; one‐time HPV screening of elderly women; and better management of screening broke previous stagnation in cervical cancer incidence rate.

Human papilloma virus vaccination and its real‐life efficacy

Endocervical sampling in women with suspected cervical neoplasia: a systematic review and meta-analysis of diagnostic test accuracy studies

Endocervical sampling in women with suspected cervical neoplasia can be performed by either endocervical brush or endocervical curettage. This study aimed to estimate the diagnostic accuracy, discomfort, and number of inadequate samples with either test. Four bibliographic databases were searched on June 9, 2022, with no date or language restrictions. We included all diagnostic studies and randomized clinical trials that compared the endocervical brush with endocervical curettage in women with an indication for colposcopy. The review protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021222406). Two authors independently screened studies, extracted data, performed the risk-of-bias assessment (Quality Assessment of Diagnostic Accuracy Studies-2), and rated the certainty of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. A meta-analysis of diagnostic test accuracy was performed using a bivariate random-effects model. We included 7 studies: 4 diagnostic cohort studies and 3 randomized clinical trials. The reference standard was conization or hysterectomy. Risk of bias and concern about applicability were high for some of the studies in patient selection and flow and timing. Overall pooled sensitivity was 81% (95% confidence interval, 48-95; 799 women; 7 studies; low quality of evidence) for endocervical brush and 70% (95% confidence interval, 42-89; 761 women; 7 studies; low quality of evidence) for endocervical curettage. Overall pooled specificity was 73% (95% confidence interval, 36-93; 799 women; 7 studies; low quality of evidence) for endocervical brush and 81% (95% confidence interval, 56-94; 761 women; 7 studies; low quality of evidence) for endocervical curettage. The risk ratio for inadequate samples with endocervical curettage compared with endocervical brush was 2.53 (95% confidence interval, 0.58-11.0; P=.215; low-certainty evidence). Two studies reported on patient discomfort; one found less discomfort in the endocervical brush group, and the other found no difference. No difference was found between endocervical brush and endocervical curettage in diagnostic accuracy, inadequate sampling rate, and adverse effects based on low-quality of evidence. Variation in the characteristics of women and the resulting diagnostic pathways make the external validity limited.

Human papillomavirus vaccination in women undergoing excisional treatment for cervical intraepithelial neoplasia and subsequent risk of recurrence: A systematic review and meta‐analysis

AbstractIntroductionIn this review and meta‐analysis we aimed to investigate whether human papilloma virus (HPV) vaccination administered after excisional treatment of cervical intraepithelial neoplasia (CIN) is associated with a reduced risk of recurrence of CIN grade 2 or worse (CIN2+).Material and methodsWe performed a systematic literature search in three online databases through June 2021. Observational studies and randomized controlled trials (RCTs) were eligible for inclusion if the prophylactic HPV vaccine was administered after excisional treatment for histologically verified CIN. Only English language literature was included. The primary outcome measure was recurrence of CIN2+ after treatment. A meta‐analysis was performed using fixed and random‐effects models, and results were reported as pooled odds ratios (OR) with 95% confidence intervals (95% CI). Quality assessment was performed using ROB2‐tool for RCTs and ROBINS‐I for observational studies. The protocol was registered in PROSPERO (CRD42021238257).ResultsA total of 1561 studies were identified, of which nine, including 19 971 women, were included. Two studies were RCTs and seven were observational studies. Using the fixed‐effect model on the two RCTs, the OR for recurrence of CIN2+ was 0.29 (95% CI 0.16–0.53). Due to considerable heterogeneity in observational studies, the random‐effects model was used to estimate pooled OR for CIN2+ recurrence in these studies. Thus, using unadjusted data from observational studies, the OR for CIN2+ recurrence was 0.35 (95% CI 0.18–0.67), whereas when using adjusted data, the OR for CIN2+ recurrence was 0.54 (95% CI 0.21–1.35). However, quality assessment revealed a serious risk of bias for the majority of the studies included.ConclusionsHPV vaccination post‐treatment was associated with a significantly reduced risk of CIN2+ recurrence when using unadjusted estimates from observational studies and RCTs. We found no significant effect of HPV vaccination on risk of CIN2+ recurrence when using the outcome measure from observational studies with the least risk of bias. Large, well‐designed randomized placebo‐controlled trials are needed to determine whether post‐treatment HPV vaccination should be recommended to all women undergoing excisional treatment for CIN.