Louise Krog

HPV vaccination following cervical intraepithelial neoplasia grade 2 diagnosis and risk of progression

Abstract Introduction Human papillomavirus (HPV) vaccination is associated with a significantly reduced risk of cervical cancer when administered before initial exposure to HPV. Women with high‐grade cervical intraepithelial neoplasia (CIN) have an increased risk of subsequent HPV‐related disease, including recurrent high‐grade CIN, compared to women without CIN. Some clinicians have advised women with high‐grade CIN to undergo HPV vaccination to reduce their subsequent risk, despite a lack of evidence for this practice. We aimed to evaluate whether HPV vaccination of women undergoing active surveillance for CIN grade 2 (CIN2) is associated with a decreased risk of progression to cervical intraepithelial neoplasia grade 3 or worse (CIN3+). Material and Methods We conducted a nationwide population‐based historical cohort study in Denmark on women aged 18–40 years undergoing active surveillance for CIN2 from 2007 to 2020. We compared women receiving at least one HPV vaccine dose within 6 months after their CIN2 diagnosis to women not receiving the vaccine. Our primary outcome was progression to CIN3+. We stratified by age at CIN2 diagnosis (18–29, 30–40), calendar year (2007–2012, 2013–2020), and index cytology (high‐grade, nonhigh‐grade). We used Cox proportional hazards regression to estimate hazard ratios of the outcomes with unvaccinated women as the reference. Age at diagnosis, calendar year, index cytology, income, and educational level were adjusted for. Results We included 4585 women, of whom 583 (12.7%) were vaccinated within 6 months after CIN2 diagnosis. A total of 1391 (30.3%) progressed to CIN3+ during follow‐up. The 5‐year cumulative risk was 29.9% (28.5–31.3). Overall, no protective effect of vaccination after CIN2 diagnosis was found (aHR 1.45 [1.24–1.69]). Stratified analyses showed increased progression risk with vaccination among women <30 years, in the early calendar period (2007–2012), and across both non‐high‐grade and high‐grade index cytology; no significant difference in risk was observed in women ≥30 years or in the latest calendar period (2013–2020). Conclusions HPV vaccination did not reduce the risk of progression in women undergoing active surveillance for CIN2. This finding indicates that HPV vaccination should not be recommended in this group of women.

High rate of persistent HPV detection after diagnostic cervical excision in older screen‐positive women

AbstractIntroductionDiagnostic work‐up of older women with a positive cervical cancer screening test is often challenging due to incomplete visualization of the transformation zone. To reduce the risk of missing disease, a diagnostic cervical excision may be performed. However, little is known on treatment efficacy and post‐treatment surveillance for older women. We aimed to investigate the proportion of women testing negative for human papillomavirus (HPV) following a diagnostic cervical excision due to an abnormal screening test.Material and MethodsWe conducted a prospective cohort study on women aged ≥45 years who were referred for colposcopy due to an abnormal screening test between March 2019 and June 2021. All women had incomplete visualization of the transformation zone and underwent colposcopy and a diagnostic cervical excision at the first visit. Women were followed from date of excision until January 30, 2023. Follow‐up data was retrieved from the Danish Pathology Databank, and baseline characteristics were obtained from medical records. Cox regression was used on interval‐censored data to estimate crude and adjusted hazard ratios for a negative HPV test after cervical excision, stratified by histology and age.ResultsA total of 100 women underwent a diagnostic cervical excision and had at least one HPV test during follow‐up. Median age was 67.4 years, and median follow‐up time was 2.9 years. At the end of follow‐up, 70% tested HPV negative. Women with cervical intraepithelial neoplasia grade two or worse in their excision specimen were more likely to test HPV negative at the first test after cervical excision compared to women with less than cervical intraepithelial neoplasia grade two, however, not statistically significant (adjusted hazard ratio 1.69, 95% CI 0.92–3.10). Women aged 65–84 years were less likely to test HPV negative compared to women <65 years (adjusted hazard ratio 0.49, 95% CI 0.28–0.87).ConclusionsIn older women undergoing a diagnostic cervical excision, 70% tested HPV negative after 2.9 years, leaving 30% with persistent HPV positivity. More studies are needed to determine the risks associated with continued HPV positivity in the absence of high‐grade disease. Furthermore, given the absence of specific guidelines, the optimal surveillance frequency remains unknown.

Risk of progression of cervical intraepithelial neoplasia grade 2 in human papillomavirus–vaccinated and unvaccinated women: a population-based cohort study

Many countries have implemented active surveillance (ie, leaving the lesion untreated) as an option among younger women with cervical intraepithelial neoplasia grade 2 because regression rates are high and excisional treatment increases the risk for preterm birth in subsequent pregnancies. However, early identification of women at increased risk for progression to cervical intraepithelial neoplasia grade 3 or worse is important to ensure timely treatment. Because women who have received a human papillomavirus vaccine have a lower risk for cervical cancer, they may have a lower risk for progression of untreated cervical intraepithelial neoplasia grade 2 to cervical intraepithelial neoplasia grade 3 or worse. This study aimed to investigate if women who received a human papillomavirus vaccine and who are undergoing active surveillance for cervical intraepithelial neoplasia grade 2 are less likely to progress to cervical intraepithelial neoplasia grade 3 or worse when compared with women who did not receive the vaccine. We conducted a population-based cohort study in Denmark using data from national health registers. We identified all women aged 18 to 40 years who were undergoing active surveillance for cervical intraepithelial neoplasia grade 2 from January 1, 2007, to December 31, 2020. Women with a previous record of cervical intraepithelial neoplasia grade 2 or worse, hysterectomy, or a loop electrosurgical excision procedure were excluded. Exposure was defined as having received ≥1 dose of a human papillomavirus vaccine at least 1 year before the cervical intraepithelial neoplasia grade 2 diagnosis. We used cumulative incidence functions to estimate the risk for progression to cervical intraepithelial neoplasia grade 3 or worse within 28 months using hysterectomy, emigration, and death as competing events. We used modified Poisson regression to calculate crude and adjusted relative risks of progression during the 28-month surveillance period. Results were stratified by age at vaccination and adjusted for index cytology, disposable income, and educational level. The study population consisted of 7904 women of whom 3867 (48.9%) were vaccinated at least 1 year before a diagnosis of cervical intraepithelial neoplasia grade 2. At the time of cervical intraepithelial neoplasia grade 2 diagnosis, women who were vaccinated were younger (median age, 25 years; interquartile range, 23-27 years) than those who were not (median age, 29 years; interquartile range, 25-33 years). The 28-month cumulative risk for cervical intraepithelial neoplasia grade 3 or worse was significantly lower among women who were vaccinated before the age of 15 years (22.9%; 95% confidence interval, 19.8-26.1) and between the ages of 15 and 20 years (31.5%; 95% confidence interval, 28.8-34.3) when compared with women who were not vaccinated (37.6%; 95% confidence interval, 36.1-39.1). Thus, when compared with women who were not vaccinated, those who were vaccinated before the age of 15 years had a 35% lower risk for progression to cervical intraepithelial neoplasia grade 3 or worse (adjusted relative risk, 0.65; 95% confidence interval, 0.57-0.75), whereas women who were vaccinated between the ages of 15 and 20 years had a 14% lower risk (adjusted relative risk, 0.86; 95% confidence interval, 0.79-0.95). For women who were vaccinated after the age of 20 years, the risk was comparable with that among women who were not vaccinated (adjusted relative risk, 1.02; 95% confidence interval, 0.96-1.09). Women who were vaccinated and who were undergoing active surveillance for cervical intraepithelial neoplasia grade 2 had a lower risk for progression to cervical intraepithelial neoplasia grade 3 or worse during 28 months of follow-up when compared with women who were not vaccinated but only if the vaccine was administered by the age of 20 years. These findings may suggest that the human papillomavirus vaccination status can be used for risk stratification in clinical management of cervical intraepithelial neoplasia grade 2.