Abstract
Background
The primary goal of human papillomavirus (HPV) vaccination is to reduce morbidity and mortality from HPV-associated disease, especially cervical cancer. We determined the ...real-world effectiveness of HPV vaccination against cervical cancer.
Methods
The study included women aged 17-30 years living in Denmark October 2006-December 2019. From nationwide registries, information on HPV vaccination and cervical cancer diagnoses were retrieved. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for cervical cancer according to vaccination status were estimated using Poisson regression with HPV vaccination treated as a time-varying variable and stratified by age at vaccination. We adjusted for attained age, education, and ethnicity. To address the effect of prevalent disease, different buffer periods were used, with 1-year buffer period as primary analysis.
Results
The cohort comprised 867 689 women. At baseline, 36.3% were vaccinated at age 16 years and younger, and during follow-up, 19.3% and 2.3% were vaccinated at ages 17-19 years and 20-30 years, respectively. For women vaccinated at ages 16 years and younger or 17-19 years, the IRRs of cervical cancer were 0.14 (95% CI = 0.04 to 0.53) and 0.32 (95% CI = 0.08 to 1.28), respectively, compared with unvaccinated women. In women aged 20-30 years at vaccination, the incidence rate was higher than among unvaccinated women (IRR = 1.19, 95% CI = 0.80 to 1.79) but slightly decreased with increasing buffer period (IRR = 0.85, 95% CI = 0.55 to 1.32, with 4-year buffer period).
Conclusion
HPV vaccine effectiveness against cervical cancer at the population level is high among girls vaccinated younger than age 20 years. The lack of immediate effect in women vaccinated at age 20-30 years points to the importance of early age at vaccination.
Background Infection with high-risk human papillomavirus (HPV) is the main cause of high-grade cervical intraepithelial neoplasia (CIN) and cancer. It has been suggested that information about ...high-risk HPV type–specific infection might make cervical cancer screening more effective. Persistent HPV infection could also be a useful screening marker. We estimated the long-term risk of high-grade CIN after one-time detection of high-risk HPV DNA and after persistent infection with individual high-risk HPV types. Methods A cohort of 8656 women from the general population of Denmark was examined twice, 2 years apart (first study examination: May 15, 1991, to January 31, 1993; second study examination: October 1, 1993, to January 31, 1995). The women underwent a gynecological examination and cervical cytology and had swabs taken for HPV DNA analysis by the Hybrid Capture 2 and line probe assays. The women were followed up through the nationwide Danish Pathology Data Bank for cervical neoplasia for up to 13.4 years. The absolute risk of developing cervical lesions before a given time was estimated as a function of time. Results For women with normal cytological findings who were concurrently HPV16 DNA positive at the second examination, the estimated probability of developing CIN grade 3 (CIN3) or worse within 12 years of follow-up was 26.7% (95% confidence interval CI = 21.1% to 31.8%). The corresponding risks among those infected with HPV18 was 19.1% (95% CI = 10.4% to 27.3%), with HPV31 was 14.3% (95% CI = 9.1% to 19.4%), and with HPV33 was 14.9% (95% CI = 7.9% to 21.1%). The absolute risk of CIN3 or worse after infection with high-risk HPV types other than HPV16, HPV18, HPV31, or HPV33 was 6.0% (95% CI = 3.8% to 8.3%). The estimated absolute risk for CIN3 or cancer within 12 years of the second examination among women who were HPV16 DNA positive at both examinations was 47.4% (95% CI = 34.9% to 57.5%); by contrast, the risk of CIN3 or worse following a negative Hybrid Capture 2 test was 3.0% (95% CI = 2.5% to 3.5%). Conclusion HPV16, HPV18, HPV31, and HPV33 infection and especially HPV16 persistence were associated with high absolute risks for progression to high-grade cervical lesions. The results indicate the potential value of genotyping in cervical cancer screening. Given that HPV DNA–negative women retained their low risk of CIN3 or worse for many years, frequent screening of these women may be unnecessary.
Abstract
Background
Vaccination against human papillomavirus (HPV) has proven to be effective against severe cervical lesions and genital warts, whereas no previous study has provided real-world data ...on the HPV vaccine effectiveness against high-grade vulvovaginal lesions.
Methods
A cohort of all women age 17-26 years living in Denmark during 2006-2019 was followed in nationwide registers for individual-level information about HPV vaccination and first diagnoses of vulvar and vaginal high-grade squamous intraepithelial lesions (HSIL+) or worse. The cumulative incidence of vulvar and vaginal HSIL+, respectively, was estimated with the Aalen-Johansen estimator, and Cox proportional hazards regression was used to estimate hazard ratios (HRs) for vulvar and vaginal lesions separately, comparing women vaccinated at age 16 years or younger and at age 17-26 years with unvaccinated women.
Results
The cohort consisted of 514 537 women, of which 50.6% were vaccinated at baseline (<16 years), 31.8% were vaccinated during follow-up (17-26 years), and 17.6% remained unvaccinated. The cumulative incidence was less than 0.6‰ for vulvar HSIL+ and less than 0.2‰ for vaginal HSIL+. Adjusted analyses showed reduced HRs for both vulvar (HR = 0.22, 95% confidence interval = 0.13 to 0.38) and vaginal HSIL+ (HR = 0.16, 95% confidence interval = 0.04 to 0.55) for women vaccinated at age 16 years or younger compared with unvaccinated women. For women vaccinated at 17-26 years of age, the reductions in HRs were smaller for vaginal HSIL+ and close to 0 for vulvar HSIL+.
Conclusions
HPV vaccination before 17 years of age reduces the risk of vulvar and vaginal HSIL+ based on real-world data.
Nonmelanoma skin cancer (NMSC) is the most common cancer among Caucasian populations worldwide, and incidence rates are increasing. However, NMSC data are not routinely collected by cancer ...registries, but Denmark has extensive registration of NMSC in two nationwide population‐based registries. We assessed incidence trends of NMSC in Denmark from 1978 to 2007. Data for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) were obtained from the Danish Cancer Registry and the Danish Registry of Pathology. For both genders, age‐specific incidence rates and overall incidence rates, age‐adjusted according to the World standard population were calculated based on combined data from the two registries. For both genders, a high increase in both BCC and SCC incidence was observed over time. Between 1978 and 2007, the age‐adjusted BCC incidence increased from 27.1 to 96.6 cases per 100,000 person‐years for women and from 34.2 to 91.2 cases for men. The SCC incidence increased from 4.6 to 12.0 cases per 100,000 person‐years for women and from 9.7 to 19.1 cases for men. For both BCC and SCC, women experienced a higher average annual percentage incidence change than men. Furthermore, the average annual percentage change in BCC incidence among persons below 40 years was significantly higher compared to older persons, especially for women. These trends may lead to an alarming NMSC incidence increase over time as population ages and will have major implications for future healthcare services. Our findings underline the need for improved preventive strategies to hamper the increasing NMSC incidence.
Abstract
Background
A reduced, 2-dose schedule of human papillomavirus (HPV) vaccination has been endorsed for preadolescent women on the basis of immunogenicity data from randomized trials, and ...limited data suggest that even 1 dose may provide sufficient protection. Surveillance of the impact of <3 vaccine doses on clinical endpoints in the targeted age group is warranted.
Methods
We conducted a nationwide cohort study of all women aged 17–25 years, living in Denmark between 2006 and 2016. From nationwide registries, we extracted individual-level data on vaccination with the quadrivalent HPV (qHPV) vaccine at 16 years or younger, number of doses administered, diagnoses of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+), and potential confounders. Using Poisson regression, we estimated incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for CIN2+ and CIN3+, according to vaccination status.
Results
The cohort comprised 590 083 women, of which 215 309 (36%) women were vaccinated at ≤16 years, and among these, 40 742 (19%) received <3 vaccine doses. A total of 5561 women had a diagnosis of CIN3+. We found considerable vaccine effectiveness against CIN3+ after 1 (IRR, 0.38 95% CI, .14–.98), 2 (IRR, 0.38 95% CI, .22–.66), or 3 (IRR, 0.37 95% CI, .30–.45) vaccine doses, compared to unvaccinated women. Results were similar for CIN2+.
Conclusions
We find substantial effectiveness of qHPV vaccination against high-grade cervical precancerous lesions, among women vaccinated with 1, 2, or 3 doses at ≤16 years of age. One-dose vaccination appeared to provide similar protection as 3-dose vaccination.
In a population-based cohort study among young women in Denmark, administration of 1 dose and 2 doses of the qHPV vaccine at age ≤16 years provides similarly high protection against high-grade cervical precancerous lesions, compared to 3 vaccine doses.
Objective
According to the recent theories on the ovarian cancer origin, any protective effect of tubal ligation may vary with histologic subtype of ovarian cancer. Furthermore, bilateral ...salpingectomy may represent an opportunity for surgical prevention of serous ovarian cancer.
Design
Nationwide register‐based case–control study.
Setting
Denmark during 1982–2011.
Population
Cases were all Danish women diagnosed with epithelial ovarian cancer (n = 13 241) or borderline ovarian tumor (n = 3605) in the study period. Age‐matched female population controls were randomly selected by risk set sampling. We required that cases and controls have no previous cancer and that controls have no previous bilateral oophorectomy.
Methods
Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals, adjusting for potential confounders.
Main outcome measures
Epithelial ovarian cancer and borderline ovarian tumors stratified according to histology.
Results
Tubal ligation reduced overall epithelial ovarian cancer risk (odds ratios 0.87; 95% confidence interval 0.78–0.98). We observed significant risk variation according to histology (p = 0.003) with the strongest risk reductions associated with endometrioid cancer (odds ratios 0.66; 95% confidence interval 0.47–0.93) and epithelial ovarian cancer of “other” histology (odds ratios 0.60; 95% confidence interval 0.43–0.83). Tubal ligation was not associated with risk of borderline ovarian tumors. Finally, bilateral salpingectomy reduced epithelial ovarian cancer risk by 42% (odds ratios 0.58; 95% confidence interval 0.36–0.95).
Conclusions
We confirmed that tubal ligation reduces the risk of epithelial ovarian cancer and particularly endometrioid cancer. To our knowledge, this is the first observational publication to report on salpingectomy and ovarian cancer risk and our promising findings warrant further investigation.
Objective
To investigate whether paracetamol use is associated with a reduced risk of epithelial ovarian cancer (EOC).
Design
A nationwide nested case–control study.
Setting
Danish female population.
...Population
A total of 9589 EOC cases diagnosed from 2000 to 2019 were age‐matched with 383 549 randomly selected female controls using risk set sampling.
Methods
Paracetamol use, reproductive history, history of medication and history of surgery were retrieved from Danish national registers. Paracetamol use was defined as at least two prescriptions for up to 1 year before the index date, and was further classified according to recency, duration, cumulative dose and intensity of dose.
Main outcome measures
Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between paracetamol and EOC risk, overall and by histological subtypes.
Results
‘Ever’ use of paracetamol was associated with a reduced EOC risk after adjusting for potential confounding factors (OR 0.92, 95% CI 0.87–0.97). The association was only significant among recent users (OR 0.89, 95% CI 0.84–0.95). The risk declined further with the increasing level of cumulative dose and intensity; women from the group with a high cumulative dose and a high intensity had a 13% (OR 0.87, 95% CI 0.80–0.94) and 14% (OR 0.86, 95% CI 0.79–0.93) reduced risk, respectively. In the histological subtype analysis, reduced risk with ‘ever’ use was most pronounced for serous and clear cell tumours.
Conclusions
Paracetamol use was associated with a decreased risk of EOC in a dose–response manner. Future studies are needed to validate the findings and investigate the mechanisms behind the association.
Abstract
Background
Increasing evidence suggests that 1-dose human papillomavirus (HPV) vaccination may protect significantly against HPV-related disease. We provide nationwide, real-world data on ...the risk of genital warts (GWs) after <3 vaccine doses.
Methods
All Danish women born in 1985–2003 were identified, and individual-level vaccination data were retrieved. The cohort was followed up for first occurrence of GWs until 31 December 2016. Using Poisson regression, we calculated incidence rates (IRs) of GWs per 100 000 person-years and IR ratios (IRRs) with corresponding 95% confidence intervals (CIs) for GWs, according to vaccination status, age at first dose, and calendar time.
Results
The cohort comprised 1 076 945 girls and women, of whom 485 408 were vaccinated. For girls initiating vaccination at age 12–14 years and 15–16 years, 1-dose vaccine effectiveness (VE) was 71% (IRR = 0.29; 95% CI, .22–.38) and 62% (0.38; .29–.49), respectively, compared with unvaccinated girls. In the same age groups, 2-dose VE was 78% (IRR, 0.22; 95% CI, .18–.26) and 68% (0.32; .26–.38), respectively. After 2009, the IRRs for 3 versus 1 dose and 2 versus 1 dose increased towards unity over calendar time, being 0.69 (95% CI, .57–.84) and 0.86 (.68–1.08) in 2016, respectively.
Conclusions
In this study, 1 or 2 doses of quadrivalent HPV vaccine was associated with substantial protection against GWs in girls vaccinated at age ≤16 years. The 1-dose VE approached that of 3 or 2 doses over calendar time, probably reflecting the impact of herd protection.
Real-world 1- and 2-dose quadrivalent human papillomavirus vaccine effectiveness (VE) was substantial in girls vaccinated at age ≤16 years. The 1-dose VE approached that of 3 or 2 doses over time, most likely reflecting the impact of herd protection.
Prophylactic human papillomavirus (HPV) vaccination programs constitute major public health initiatives worldwide. We assessed the global effect of quadrivalent HPV (4vHPV) vaccination on HPV ...infection and disease. PubMed and Embase were systematically searched for peer-reviewed articles from January 2007 through February 2016 to identify observational studies reporting the impact or effectiveness of 4vHPV vaccination on infection, anogenital warts, and cervical cancer or precancerous lesions. Over the last decade, the impact of HPV vaccination in real-world settings has become increasingly evident, especially among girls vaccinated before HPV exposure in countries with high vaccine uptake. Maximal reductions of approximately 90% for HPV 6/11/16/18 infection, approximately 90% for genital warts, approximately 45% for low-grade cytological cervical abnormalities, and approximately 85% for high-grade histologically proven cervical abnormalities have been reported. The full public health potential of HPV vaccination is not yet realized. HPV-related disease remains a significant source of morbidity and mortality in developing and developed nations, underscoring the need for HPV vaccination programs with high population coverage.
Vulvar cancer is rare, but causes substantial morbidity in affected patients. A subset of vulvar cancers is caused by high‐risk human papillomavirus (hrHPV), which primarily exerts its oncogenic ...effect through upregulation of tumor suppressor protein p16. Tumors positive for both hrHPV and p16 (double positive) are assumed to be HPV‐driven, but only few large studies have investigated the combined prevalence of hrHPV and p16 positivity in vulvar cancer over time. In this Danish cross‐sectional study, we assessed the prevalence of p16 positivity and double positivity for hrHPV and p16 in a large sample of vulvar squamous cell carcinomas (VSCCs) diagnosed during 1990 to 2017. In a nationwide register, we identified VSCCs from 13 hospitals across Denmark, and collected archival tumor tissue for hrHPV testing with INNO‐LiPA and immunohistochemical p16 staining. We calculated the prevalence of hrHPV, p16 positivity and double positivity according to time, age and histological subtype and evaluated time trends through estimated annual percentage changes. We included 1278 VSCCs. Overall, 35.0% (95% confidence interval CI: 32.4‐37.6) were positive for p16 and 31.0% (95% CI: 28.4‐33.5) were positive for both hrHPV and p16. The prevalence of p16 positivity and double positivity increased over time, both in women aged ≤59 and ≥60 years. The double positive prevalence was higher in nonkeratinizing (60.7%) and warty/basaloid VSCCs (67.5%) than in keratinizing (16.1%) and verrucous VSCCs (5.0%). These results indicate that approximately one‐third of vulvar cancers were caused by hrHPV infection, supporting a substantial preventive potential of the HPV vaccine.
What's new?
A subset of vulvar cancers is caused by high‐risk human papillomavirus (HPV), which primarily exerts its oncogenic effect through upregulation of tumor suppressor protein p16. How the proportion of HPV‐driven vulvar cancers has changed over time remains largely unexplored. This Danish cross‐sectional study estimated HPV prevalence and p16 positivity in more than 1200 vulvar cancer cases diagnosed in 1990 to 2017. The proportion of HPV‐driven tumors (ie, positive for both HPV and p16) increased to 35.7% in the most recent period. The findings support the potential of HPV vaccination to substantially prevent vulvar cancer.
PDF
