A novel method for continuous measurements of clinical practice guideline adherence.

Introduction: Clinical practice guidelines (hereafter 'guidelines') are crucial in providing evidence-based recommendations for physicians and multidisciplinary teams to make informed decisions regarding diagnostics and treatment in various diseases, including cancer. While guideline implementation has been shown to reduce (unwanted) variability and improve outcome of care, monitoring of adherence to guidelines remains challenging. Real-world data collected from cancer registries can provide a continuous source for monitoring adherence levels. In this work, we describe a novel structured approach to guideline evaluation using real-world data that enables continuous monitoring. This method was applied to endometrial cancer patients in the Netherlands and implemented through a prototype web-based dashboard that enables interactive usage and supports various analyses. Method: The guideline under study was parsed into clinical decision trees (CDTs) and an information standard was drawn up. A dataset from the Netherlands Cancer Registry (NCR) was used and data items from both instruments were mapped. By comparing guideline recommendations with real-world data an adherence classification was determined. The developed prototype can be used to identify and prioritize potential topics for guideline updates. Results: CDTs revealed 68 data items for recording in an information standard. Thirty-two data items from the NCR were mapped onto information standard data items. Four CDTs could sufficiently be populated with NCR data. Conclusion: The developed methodology can evaluate a guideline to identify potential improvements in recommendations and the success of the implementation strategy. In addition, it is able to identify patient and disease characteristics that influence decision-making in clinical practice. The method supports a cyclical process of developing, implementing and evaluating guidelines and can be scaled to other diseases and settings. It contributes to a learning healthcare cycle that integrates real-world data with external knowledge.

Risk prediction of cervical abnormalities: The value of sociodemographic and lifestyle factors in addition to HPV status.

High-risk human papillomavirus (hrHPV) assessment as a primary screening test improves sensitivity but decreases specificity. Determining risk for cervical abnormalities and adapting policy accordingly may improve the balance between screening benefits and harms. Our aim is to assess the value of factors other than HPV in prediction of cervical abnormalities. Data from a Dutch prospective cohort were used. Women aged 18-29 years, not yet eligible for screening, were included in 2007. Data collection consisted of a questionnaire and a cervicovaginal self-sample. Linkage with PALGA (pathology database) was performed in 2017. The analyses included 1483 women. The full model, including sociodemographic and lifestyle factors, was compared to the null model, including baseline HPV only. The outcome of interest was cervical intraepithelial neoplasia 2 or worse (CIN2+). There were 86 women with CIN2+. Baseline hrHPV status was an important predictor (OR = 5.20, 95%CI = 3.27-8.27). The area under the ROC curve (AUC) of the null model was 0.67 (95%CI = 0.61-0.72). The full model had a slightly higher AUC of 0.73 (95%CI = 0.67-0.79). Bootstrap validation indicated that overfitting was present. This exploratory study has confirmed that a single hrHPV measurement is a strong predictor of cervical abnormalities, and additional risk factors in young women appeared to have limited added value. However, prediction based on hrHPV only does leave room for improvement. Future studies should therefore focus on women in the screening age range and search for other predictors to further enhance risk prediction. Adapting policy based on risk may eventually help optimise screening performance.

Screening for persistent high-risk HPV infections may be a valuable screening method for young women; A retrospective cohort study.

INTRODUCTION: Screening of young women is often discouraged because of the high risk of unnecessary diagnostics or overtreatment. Multiple countries therefore use cytology instead of high risk human papillomavirus (hrHPV)-testing as screening method for young women because of the limited specificity of hrHPV-testing. The objective of this study was to investigate how hrHPV screening before the age of 30, can be used to reduce the future prevalence of high-grade cervical lesions in young women. METHODS: We retrospectively analyzed follow-up data from a cohort study on HPV prevalence in unscreened Dutch women aged 18-29 years. Women performed multiple self-collected cervico-vaginal samples for HPV detection and genotyping. At least one valid cervical pathology result was obtained from 1,018 women. Women were categorized as hrHPV negative, cleared- or persistent hrHPV infection. Anonymized follow-up data for each group was obtained. Composite outcome measures were defined as; normal, low-grade squamous intraepithelial lesion (LSIL) or high-grade squamous intraepithelial lesion (HSIL). The association between prior hrHPV status and cytology and histology outcome was analyzed. RESULTS: After exclusion, a pathology result was registered for 962 women. The prevalence of HSIL was 19.3% in women with a persistent HPV infection at a younger age. This is significantly higher (p<0,001) compared with the HSIL prevalence of 1.5% in HPV-negative women, and 3.1% (n = 8) in women who cleared the hrHPV infection in the past. CONCLUSION: Women with a persistent hrHPV infection in their 20s, show an increased prevalence of HSIL lesions in their early 30s. Screening for persistent hrHPV infections, instead of cytology screening before the age of 30, can be used to reduce the future prevalence of cervical cancer in young women.

Human papillomavirus detection in pregnant women: a prospective matched cohort study.

OBJECTIVE: To study the prevalence, incidence, and clearance of human papillomavirus (HPV) in pregnant and nonpregnant women. METHODS: In this prospective matched cohort study, 51 women, became pregnant during follow-up of an HPV epidemiology study (n=2065), and 51 matched nonpregnant women were included. All women provided 3-monthly cervicovaginal self-samples and completed a questionnaire. The PCR SPF(10) LiPA(25) was used for HPV testing. Matching was performed using a propensity score. RESULTS: The cumulative prevalence of high-risk HPV (hrHPV) was 19.6% (n=10) of the pregnant and 17.6% (n=9) of the matched control women. The time point prevalence of any type HPV and hrHPV was not significantly different for pregnant and matched control women. After baseline, there were 10 newly detected hrHPV types in 6 (11.8%) of the pregnant women, and there were 11 newly detected hrHPV types in 8 (15.7%) of the matched control women. There was no difference in HPV clearance between pregnant and matched control women. CONCLUSIONS: This study shows that in a low-parity population of young, unscreened women, pregnancy does not seem to influence HPV prevalence, incidence, and clearance.

Human papillomavirus persistence in young unscreened women, a prospective cohort study.

OBJECTIVE: To evaluate hr-HPV persistence and associated risk factors in a prospective cohort of young unscreened women. Additionally, the relation between hr-HPV status and cytology/histology results is examined. METHODS AND PRINCIPAL FINDINGS: Two year follow-up of 235 out of 2065 young women (18-29 years), participating in a large, one year epidemiological study, with questionnaires, self-collected cervico-vaginal samples (Vibabrush), and SPF(10)LiPA for HPV detection. Only women hr-HPV positive at sample month 12 were invited for a second year of follow-up. After study follow-up, available cytology/histology data were requested from PALGA (the national network and registry of histo- and cytopathology in The Netherlands). These data were compared with available cytology/histology data of the month 12 hr-HPV negative women from the same cohort. 44.1% of the hr-HPV types detected at study month 12, persisted during follow-up. HPV types 45, 31, 16 and 18 were most likely to persist with percentages of 60.0%, 56.8%, 54.4%,and 50.0%, respectively. Compared to newly detected infections at month 12, infections present since 6 months or baseline had an increased risk to persist (OR 3.09 [95% CI: 1.74-5.51] and OR 4.99 [95% CI: 2.67-9.32], respectively). Other co-factors influencing persistence were, multiple HPV infections, smoking and multiple lifetime sexual partners. The percentage of women with a HSIL/CIN2+ (12.1%) in the persistent HPV group, was not significantly different (p = 0.107) from the 5.3% of the women who cleared the hr-HPV infection, but was significantly (p 0.000) higher than to the 1.6% of women in the hr-HPV negative control group. CONCLUSION: We showed that HPV genotype, multiple infections, smoking, and multiple lifetime sexual partners are co-factors that increase the risk of hr-HPV persistency. Most importantly, we showed that hr-HPV infections are more likely to persist the longer they have been present and that women with a persistent hr-HPV infection have a high risk of HSIL/CIN2+ development.

Co-administration of human papillomavirus-16/18 AS04-adjuvanted vaccine with hepatitis B vaccine: randomized study in healthy girls.

BACKGROUND: To evaluate co-administration of GlaxoSmithKline Biologicals' human papillomavirus-16/18 AS04-adjuvanted vaccine (HPV) and hepatitis B vaccine (HepB). METHODS: This was a randomized, controlled, open, multicenter study. Healthy girls, aged 9-15 years, were randomized to receive HPV (n=247), HepB (n=247) or HPV co-administered with HepB (HPV+HepB; n=247) at Months 0, 1 and 6. Antibodies against hepatitis B surface antigen (HBs), HPV-16 and HPV-18 were measured, and reactogenicity and safety monitored. Co-primary objectives were to demonstrate non-inferiority of hepatitis B and HPV-16/18 immune responses at Month 7 for co-administered vaccines, compared with vaccines administered alone, in the according-to-protocol cohort. RESULTS: The pre-defined criteria for non-inferiority were met for all co-primary immunogenicity endpoints at Month 7. Anti-HBs seroprotection rates ≥10mIU/mL were achieved by 97.9% and 100% of girls, respectively, following co-administration or HepB alone. Anti-HBs geometric mean titers (GMTs) (95% confidence interval) were 1280.9 (973.3-1685.7) and 3107.7 (2473.1-3905.1) milli-international units/mL, respectively. Anti-HPV-16 and -18 seroconversion rates were achieved by ≥99% of girls following co-administration or HPV alone. Anti-HPV-16 GMTs were 19819.8 (16856.9-23303.6) and 21712.6 (19460.2-24225.6) ELISA units (ELU)/mL, respectively. Anti-HPV-18 GMTs were 8835.1 (7636.3-10222.1) and 8838.6 (7948.5-9828.4) ELU/mL, respectively. Co-administration was generally well tolerated. CONCLUSIONS: The study results support the co-administration of HPV-16/18 AS04-adjuvanted vaccine with hepatitis B vaccine in adolescent girls aged 9-15 years. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration number NCT00652938.

The indicating FTA elute cartridge a solid sample carrier to detect high-risk HPV and high-grade cervical lesions.

The clinically validated high-risk human papillomavirus (hrHPV) Hybrid Capture 2 (HC2) and GP5+/6+-PCR assays were analyzed on an Indicating FTA Elute cartridge (FTA cartridge). The FTA cartridge is a solid dry carrier that allows safe transport of cervical samples. FTA cartridge samples were compared with liquid-based samples for hrHPV and high-grade cervical intraepithelial neoplasia (CIN) detection. One cervical sample was collected in a liquid-based medium, and one was applied to the FTA cartridge. DNA was eluted directly from the FTA cartridge by a simple elution step. HC2 and GP5+/6+-PCR assays were performed on both the liquid-based and the FTA-eluted DNA of 88 women. Overall agreement between FTA and liquid-based samples for the presence of hrHPV was 90.9% with GP5+/6+-PCR and 77.3% with HC2. The sensitivity for high-grade CIN of hrHPV testing on the FTA cartridges was 84.6% with GP5+/6+-PCR and only 53.8% with HC2. By comparison, these sensitivities on liquid-based samples were 92.3% and 100% for GP5+/6+-PCR and HC2, respectively. Therefore, the FTA cartridge shows reasonably good overall agreement for hrHPV detection with liquid-based media when using GP5+/6+-PCR but not HC2 testing. Even with GP5+/6+-PCR, the FTA cartridge is not yet capable of detecting all high-grade CIN lesions.

The potential role of self-sampling for high-risk human papillomavirus detection in cervical cancer screening.

High-risk human papillomavirus (hr-HPV) detection will become an important tool in the screening for cervical cancer. Self-sampling is an inexpensive and well-accepted method for HPV detection that will increase participation of nonresponders in current screening programs. Even more, because self-collected samples are as good as physician-collected samples for HPV detection, self-sampling might be a suitable method for future primary cervical cancer screening.

Effect of the menstrual cycle and hormonal contraceptives on human papillomavirus detection in young, unscreened women.

OBJECTIVE: To estimate the effect of the menstrual cycle and oral contraceptive pill (OCP) use on the prevalence, incidence, and persistence of human papillomavirus (HPV). METHODS: A longitudinal study was conducted among 2,065 women aged 18-29 years. The women returned a self-collected cervicovaginal sample and filled out a questionnaire. A total of 1,812 women participated at all three time points, month 0, month 6, and month 12. RESULTS: Low- and high-risk HPV prevalence at study entry was 8.9% and 11.8%, respectively. The annual incidence of low-risk HPV infections was 12.5% and the persistence was 2.0%. For high-risk HPV, the incidence and persistence was 12.1% and 4.5%, respectively. These results did not differ between OCP users and nonusers. A significant relationship between high-risk HPV detection and the timing of sampling was found when OCP users and nonusers were analyzed separately. In the second half of the menstrual cycle, high-risk HPV detection decreased in nonusers (P=.007) and increased in OCP users (P=.021). When women used OCPs continuously, high-risk HPV detection returned to the level of the first half of the menstrual cycle. CONCLUSION: High-risk HPV detection was significantly influenced by sample timing in the menstrual cycle when analyzed separately for OCP users and women with a natural menstrual cycle. This may have implications in the future, when high-risk HPV detection may become a primary screening tool in cervical cancer prevention. LEVEL OF EVIDENCE: II.