Human papillomavirus (HPV) screening has significantly reduced cervical cancer (CC) mortality. Women who consecutively test positive for high-risk HPV without and minor changes on reflex cytology  or dysplasia on cervical colposcopy-oriented biopsy are always referred to colposcopy. The aim of the present study was to assess whether this guidance is appropriate for COBAS HPV testing with reflex cytology. A cross-sectional, retrospective study was carried out in 5,227 women who underwent routine CC screening over a period of five years (2012-2017). All HPV tests were performed using Cobas®4800 HPV. The study included women attending gynecology appointments whose first HPV test was positive and who had any type of follow-up. Patients’ HPV test results as well as cytology and biopsy findings obtained during the abovementioned period were analyzed. A descriptive and comparative statistical study was conducted using this data. A total of 765 out of 6003 HPV tests performed in 5,227 women were positive, and 141 women who had a positive HPV test  repeated the HPV test at least once. Of these 141 women, 6 were diagnosed with high-grade squamous intraepithelial lesion (HSIL) during the follow-up period. All cases of HSIL were diagnosed after the second HPV test. This study shows that, at cervical cancer screening, all women testing positive for HPV regardless of Pap smear result should be referred to colposcopy. According to the World Health Organization (WHO) statistics, around 15 to 20% of the diagnosed cancers are associated with viral infections. Human papillomavirus (HPV) is one of the viruses contributing to these statistics, increasing the risk of cervical cancer (CC) progression when high-risk HPV infection persists . CC is the fourth most common cancer in women worldwide, after breast cancer, colorectal cancer and lung cancer .Screening programs which incorporate HPV testing have consistently been associated with a reduction in CC incidence, potentially decreasing morbidity and mortality . Nevertheless, CC remains a major public health problem, with estimated 569,847 new cases and 311,365 deaths worldwide in 2018 .Persistent infection with high-risk HPV genotypes is a necessary but not sufficient condition for disease progression and is the main epidemiological driver of high-grade intraepithelial lesions (HSIL) and invasive carcinoma . HPV infection is subclinical in most cases, especially in younger women where in more than 80% of cases the infection resolves spontaneously within 1 to 2 years. However, approximately 10% of HPV infections can become persistent and about 3 to 4% progress to intraepithelial lesions. Of these, 0.7 to 1% may advance to high-grade lesions (CIN 2/3), being estimated that 0.1% will progress to invasive cancer if not detected and treated in a timely manner .The natural course of CC is well known, and its carcinogenesis process is slow. The presence of CC precursor lesions, the availability of sensitive screening tests for detection and effective treatment methods have enabled highly effective secondary prevention, using screening programs .The most common CC screening methods are conventional cytology, liquid-based cytology and HPV testing, or an association of the latter two . The “standard” screening method has been morphological cytology. Several studies have shown that HPV testing is more sensitive than cytology alone in detecting and preventing high-grade lesions and progression to cancer. In addition, when using HPV testing as a screening method, the presence of a negative test allows the screening interval to be extended to 5 years, improving compliance with screening programs and enabling effective cost reductions of approximately 20% .In 2017, a national organized CC HPV-based screening program was implemented in Portugal for women between the ages of 25 and 60 years, performed every 5 years, with reflex cytology for high-risk HPV genotypes other than HPV 16 and 18. This screening program introduces updates to the previous regional cervical cancer screening programs and states that women with a positive HPV test for genotypes other than 16 and 18 with negative for intraepithelial lesion or malignancy (NILM) cytology should repeat the HPV test within the following year. In case of a second HPV test is positive, the woman will be referred for colposcopy. Following 2013 Kaiser Permanent Northern California (KPNC) study results, women with a repetitive positive HPV test with without or minor cytological abnormality (ASC-US/LSIL) and no dysplasia on cervical oriented-colposcopy biopsy should be recommended to colposcopy based on co-testing and Hybrid Capture 2  for HPV testing . However, no scientific report showed whether this approach is useful on cervical cancer screenings based on primary new molecular technologies for HPV testing with reflex cytology.Our goal was to use the opportunistic CC screening program of the Cova da Beira University Hospital Center (CHUCB), based on primary COBAS HPV testing and triage cytology, to validate colposcopy recommendation for those women with repeated positive HPV test for genotypes other than HPV 16 and 18 and NILM or minor lesions on previous cytology and no previous dysplasia detected on cervical oriented-colposcopy biopsy.A cross-sectional and retrospective study was carried out based on data from the routine CC screening protocol in force at CHUCB between August 2012 and August 2017. The screening protocol was based on HPV testing as the primary method for all women over 25 years old with no history of CC screening in the past 2 years who attend gynecology appointments at the CHUCB.®.The screening method was the Cobas®4800 HPV test, which detects HPV 16, HPV 18 and other types of HPV , using the liquid medium SurepathAll HPV tests were performed at the Laboratory of the Clinical Pathology Department of the CHUCB, while the cytological and histological tests were conducted at the Anatomical Pathology Department of the CHUCB.The CC screening program of the CHUCB was designed and implemented by the CHUCB Colposcopy Unit, where all colposcopic examination were performed. According to the CHUCB screening algorithm, shown in Of all 6,003 HPV tests performed in 5,227 women who underwent routine screening at the CHUCB over the abovementioned 5 years, 765 (14.6%) women who had a positive HPV test were selected for our study. Of these, we evaluated 141 women who had no history of treatment for cervical intraepithelial neoplasia and had satisfactory cytology findings, classified as NILM or minor cytological lesions (ASC-US/LSIL), normal colposcopy and/or no dysplasia on biopsy, and who had follow-up appointments at the Colposcopy Unit of the CHUCB. A biopsy was required during a colposcopy appointment only in the presence of grade 1 or 2 colposcopic findings or signs of invasion. If the transformation zone is classified as type 3 (squamouscolumnar junction not fully visible), endocervical curettage is performed routinely.A descriptive statistical analysis of the data was performed, using the IBM SPSS application software, version 26 . In all cases, we analyzed the patient’s age, HPV test results , and cytology and histology findings of the biopsy obtained using colposcopy.The study sample consisted of 141 women who had a positive HPV test  with reflex cytology classified as NILM or minor cytological lesions (ASC-US/LSIL), but normal colposcopy and/or no dysplasia on biopsy and who underwent follow-up . This coDuring follow-up, CIN2+ lesions were detected in six (4.3%) women, with a mean age of 35.7 years (standard deviation= 7.7), and all CIN2+ lesions were diagnosed after the second HPV test. No women were diagnosed with invasive carcinoma. The mean time to diagnosis of CIN2+ lesions was 18.5 months (standard deviation=4.2). The HPV test, cervical cytology and biopsy results are shown in The protocol used in this study was the CC screening protocol of the Gynecology Department of the CHUCB, which recommends HPV testing as the primary test in routine screening. This is an institutional screening program which, among other aspects, is open to all patients attending gynecology appointments (including pregnant women) and had the participation of all physicians who offer gynecology appointments at the CHUCB. This cervical cancer screening was implemented at the CHUCB to manage patients and to mitigate the effects of low compliance with the national screening program.The CC screening protocol at the Gynecology Department of the CHUCB beginning at 2012 was organized following 2011 ATHENA HPV study results .A high percentage of women under the age of 30 were included in the study population. The CC screening protocol in force at the CHUCB includes women over 25 years of age and some physicians did not comply with the inclusion criteria. There was a higher prevalence and spontaneous resolution of high-risk HPV infection in the group of women under 30 years of age, as well as less serious cytological and histological diagnoses, which is in accordance with the literature.®4800 HPV test, which is a qualitative test that uses real-time PCR technology to simultaneously detect DNA from 12 types of human recombinant HPV  and individually detect HPV 16 and 18. β-globin gene is amplified as an internal control. It can be used as a primary screening method with reflex cytology for positive HPV or in addition to cytology (co-testing). Thus, CIN3+ risk stratification is improved, increasing sensitivity for early detection of cervical cancer, with a negative predictive value very close to 100% .The HPV test used for screening was the Cobas®, which does not exhibit significant differences in terms of cut-off values, when compared to other certified liquid collection media, for the detection of CIN1, CIN2+ and CC lesions .The liquid medium used for transport and preservation of all samples for cytology was SurePathSome women who had a positive HPV test did not undergo follow-up because they had a surgery for a benign condition (uterine fibroids or pelvic organ prolapse corrections), or they stopped attending appointments. In accordance with literature, the percentage of multiple infections was different according to age, suggesting transient reinfection rather than a persistent infection .From the analysis of the 6 cases of HSIL diagnosed, we highlight the importance of performing colposcopy after the second test, as all our cases were diagnosed at this time. Our results are validated by other studies reporting similar situations . The second cytology was suggestive of HSIL in only two cases, and it was classified as NILM in one case, which reinforces the value of colposcopy in these situations.The absence of HSIL diagnosed after the second HPV test is probably due to the referral for colposcopy of all patients after the second positive HPV test, regardless of cytology findings. This procedure allowed HSIL identification which was not diagnosed during the first test. Between the first and second tests, it is more likely that there was regression than progression of dysplastic lesions, which may also explain in part why no other cases of HSIL were diagnosed after the second test. The outcome of any HPV-based CC screening is highly dependent on the number of lesions detected using colposcopy-directed biopsy, which reinforces the importance of quality colposcopy practices. Avoiding unnecessary biopsies without neglecting the diagnosis of cervical cancer precursor lesions is of paramount importance, and all women with positive HPV tests should be referred to different colposcopy units, as was the case in this study.This study demonstrates that women undergoing HPV-based CC screening who had one positive HPV test with NILM, ASC-US or LSIL cytology, with normal colposcopic findings and/or no dysplasia on cervical biopsy, should be referred for colposcopy in the presence of a second positive HPV test, regardless of the cytology findings. This procedure is standardized in the current cervical cancer screening program in Portugal and recommended by 2019 American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines .This study has some limitations. The CC screening method used at the CHUCB is an institutional routine program based on a random population that attends gynecology appointments and includes pregnant women, and it is not an organized screening program. Furthermore, sample size is limited as the geographic localization of CHUCB only serves a population of approximately 90,000 people which includes the municipalities of Covilhã, Fundão, Belmonte and Penamacor. Only women referred by CHUCB physicians to the CHUCB Colposcopy Unit were evaluated in this study. Many of these women had previously participated in the organized cervical cancer-screening program in the Centre Region of Portugal, which has been in place for more than 20 years. The influence of HPV vaccination on the results was not evaluated because the percentage of vaccinated women was small at the time of data collection.Nevertheless, the results of our study concerning HPV and cytology abnormalities prevalence are in agreement with studies performed in other countries, such as the HEllenic Real life Multicentric cErvical Screening study group, in Greece (HERMES)  and a study that evaluates the efficacy outcomes of primary HPV testing based on the follow-up of randomized controlled trials in Germany (WOLPHSCREEN), Sweden (SWEDESCREEN), England (ARTISTIC), the Netherlands (POBASCAM) and Italy (NTCC) . Therefore, we can conclude that our studied population was adequate for valid conclusions. In addition, our study is in agreement with recent published 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors , that recommend colposcopies for all women with repeated positive HPV testing with NILM or minor cytology abnormalities.This study has shown that, regardless of reflex cytology findings, women who have at least two consecutive positive cervical HPV tests are at increased risk of having previously undiagnosed cervical HSIL and should always be referred for colposcopy. Additionally, the risk of intraepithelial lesions or malignancy was independent of the type of HPV determined. All women with cervical repeated positive HPV testing and with absent or minor cytology abnormalities should be referred to colposcopy in an independent way of screening adopted program and technology used for HPV testing, as recommended by ASCCP.AbbreviationsASCCP – American Society for Colposcopy and Cervical Pathology; ASC-H – atypical squamous cells; ASC-US – atypical squamous cells of undetermined significance; CC – cervical cancer; CHUCB – Cova da Beira University Hospital Center; CIN – cervical intraepithelial neoplasia; Co-testing: Concomitant HPV test and cytology; HPV – human papillomavirus; HSIL – high-grade squamous intraepithelial lesion; KPNC – Kaiser Permanent Northern California; LSIL – low-grade squamous intraepithelial lesion; NILM – negative for intraepithelial lesion or malignancy; SPSS – Statistical Package for the Social Sciences.Vitor Caeiro: Conducted the investigation and write manuscript; Sara Nunes: Organize statistical analysis of data and review the manuscript; Bruno Esteves: Responsible by HPV testing and pap smear and review the manuscript; José Fonseca-Moutinho; Advisor and review the manuscript.


Background: Cervical cancer screening has shifted toward human papillomavirus (HPV)-based testing, but uptake of primary HPV screening in the United States is unknown and previous studies highlight delays in clinician adoption of guideline updates.Methods: We conducted a cross-sectional electronic survey of primary care clinicians  assessing awareness and support of primary HPV screening. We assessed factors for association with past use of HPV testing and support of clinician- and patient-collected HPV testing individually using Fisher's exact test and jointly using Firth's logistic regression.Results: Most clinicians (79%) were familiar with one or more primary HPV screening guidelines. Support for clinician-collected (89%) and patient-collected (82%) HPV testing was high, but only 34.5% reported prior use. Guideline familiarity was positively associated with HPV testing in practice (p = 0.0001). Support of clinician-collected testing was positively associated with more years in practice (p = 0.03), internal (vs. family) medicine specialty (p = 0.03), and guideline familiarity (p ≤ 0.0001). Male clinicians more frequently supported patient collection for patients overdue for screening (p = 0.013). Physicians more frequently than advanced practice providers (APPs) supported patient collection for screening-adherent women (p = 0.021). Multivariable analysis showed those unfamiliar with guidelines were less likely to have used HPV testing  or to support clinician-collected HPV testing [OR: 0.16 (0.07–0.37)]. APPs were less likely than physicians to support patient-collected HPV testing among screening-adherent women [OR: 0.42 (0.20–0.87)].Conclusions: We observed high levels of guideline awareness and clinician support for primary HPV testing, despite relatively low use. This merits further exploration to inform future interventions to increase uptake. Our study addresses gaps in knowledge about clinician awareness, support, and use of primary HPV screening, following endorsement by the USPSTF, the principal authority for practice guidelines in primary care. In addition, we assess clinician support of screening through patient self-collection.Adoption of new technologies such as primary HPV testing, per Diffusion of Innovations Theory, is impacted by attributes of the innovation, traits, and influencers of potential adopters, as well as the larger social context.We conducted an electronic cross-sectional survey of primary care clinicians and residents in Mayo Clinic practices to evaluate awareness and support of primary HPV testing for cervical cancer screening through clinician collection and patient self-collection, along with prior use of primary HPV testing in practice. The Institutional Review Board at Mayo Clinic approved this study.20 These stages, which could also be described as awareness and support of an innovation, informed the focus of our survey design. Through a literature review, we identified survey domains, including clinician awareness and knowledge of primary HPV test guidelines, beliefs about the test, influencing factors on clinical practice, prioritized test attributes, and engagement with screening. These domains were used to develop survey items and provide content validity. We included several existing survey questions with the authors' permission as described below.Knowledge of and attitude toward an innovation are foundational steps in the adoption of new interventions per the innovation-decision stages outlined in the Diffusion of Innovations theory.We developed investigator-generated questions for key survey question concepts not identified through literature review. We pretested a survey draft in the sampling frame population with probes to ensure questions were understandable and survey questions were measuring the intended concept to address construct validity.Clinician demographics, including sex, race, and ethnicity, were collected along with medical practice characteristics of primary care specialty, degree, and years in practice. To assess awareness of the USPSTF and ACS guidelines, a paragraph was embedded in the survey describing primary HPV testing and explaining current USPSTF and ACS guidelines related to primary HPV screening. Survey respondents were then asked if they were aware of USPSTF, ACS, both, or neither guideline. Clinician use of primary HPV testing in practice was assessed by self-report.21Clinicians who reported not using primary HPV testing for cervical cancer screening were asked to select one main reason from the following response options: (1) I am not comfortable with the primary HPV testing option at this time; (2) My patients would not be comfortable with primary HPV testing; (3) It is not standard practice at my clinic; or (4) Other, please specify (open-ended space provided). We also included with author permission a question from a 2015 survey of US providers asking to what extent cervical cancer screening practices were influenced by the following factors: practice guidelines, clinical experience, patient preference, and patient HPV vaccination status.22 queried respondents about attributes of patient-collected vaginal HPV tests they considered most important, support for and concerns with this approach. Clinicians answered if they strongly supported, somewhat supported, somewhat opposed, or strongly opposed the three following scenarios for cervical cancer screening: (1) clinician-collected primary HPV test as supported by USPSTF and ACS guidelines; (2) patient-collected primary HPV test for women overdue or never screened; and (3) patient-collected primary HPV test for women historically adherent to screening.We asked clinicians if they were familiar with the concept of patient self-collection of a vaginal sample for HPV testing, for cervical cancer screening. Questions modified with permission from Mao et al.Clinicians were advised to answer as if there was FDA approval for the patient collection scenarios. Currently, there are no FDA-approved HPV self-sampling kits. There are several companies in the United States that offer HPV self-sampling kits for patients, but these are unregulated and not recommended by the national cervical cancer screening guideline groups. For analysis, we dichotomized those results into “support” (strongly or somewhat) or “oppose” (somewhat or strongly).The sampling frame included all Family Medicine (FM) and Internal Medicine (IM) physicians and nurse practitioner and physician assistant providers grouped together as advanced practice providers (APP), as well as FM residents in the Mayo Clinic Primary Care practices. Administrators in coverage regions confirmed 815 clinicians/residents in the sampling frame. We obtained permission to conduct the survey from department and division chairs of FM and IM and Mayo Clinic Human Resources. As the primary outcome variables were single proportion estimates, we based the desired sample size on calculations of precision.For a 95% confidence level that the true primary outcome values were within a 5% margin of error of the reported values and using the population size of 815 and 50% population proportion, the desired sample size was calculated to be 262. We invited all identified clinicians to participate in the survey as a census study sample to target the desired sample size. Clinicians who reported not performing cervical cancer screening in their clinical practice (first question of the survey) were subsequently excluded.23 a multiple contact data collection protocol, including up to three contacts, was deployed. We sent a Qualtrics unique web survey link to the clinicians' Mayo Clinic work e-mail addresses. Two weeks later, we sent a follow-up email with a link to the web survey to nonresponders. After another 2 weeks, all remaining nonrespondents received a third and final email survey invitation and link.The Mayo Clinic Survey Research Center performed the survey administration and data collection. As per the Dillman method,Primary outcome variables included the following: (1) prior use of primary HPV testing in clinical practice; (2) support for clinician-collected primary HPV screening; (3) support for patient-collected primary HPV screening in underscreened women; and (4) support for patient-collected primary HPV screening in women historically adherent to screening .Secondary outcomes included prior use of primary HPV testing in practice and support of primary HPV testing in the three different scenarios by clinician demographics of sex, race/ethnicity, type of clinician, years in practice, clinical specialty, factors influencing cervical cancer screening practices, and awareness of guidelines.Descriptive statistics were reported for clinician demographics, practice characteristics, factors influencing cervical cancer screening practices, and USPSTF and ACS guideline awareness. In the descriptive table, we reported rates of guideline awareness by categories of USPSTF, ACS, both, or neither.In the bivariate and multivariate analyses, we grouped awareness as “yes” (aware of one or both guidelines) or “no” (aware of neither guideline). Bivariate associations between clinician characteristics and prior use of primary HPV testing in practice, and support for primary HPV testing by clinician collection and by patient self-collection in underscreened compared with screening-adherent women were tested using Fisher's exact tests due to the rarity of survey responses for some responses. We calculated confidence intervals for odds ratios (ORs) of single predictors by inverting Fisher's exact tests.To assess the simultaneous association between multiple predictors and the previously described outcomes, we first considered the correlation of predictors and selected predictors that were better targets for future intervention. Tests for pairwise association of all predictors were conducted and predictors in multivariable models were included for their actionable and practice relevance.For example, type of clinician was highly correlated with sex of the clinician. Future educational interventions would more appropriately be targeted based on clinician type (physician/resident vs APP) rather than by clinician sex, so sex was dropped as a predictor variable. In addition, a high correlation was observed among type of clinician, years of experience, and clinical specialty; targeting an intervention to the type of clinician would be more feasible than targeting years of experience.For the multivariate models, we only included variables that were significant for at least one of the outcomes in the bivariate analysis: clinician type, influence of practice guidelines, and guideline familiarity. We used Firth's logistic regression to model the outcomes with the selected predictors due to rarity of one of the categories of the outcomes; also, Firth's logistic regression, being a penalized regression model, is more stable in the presence of correlated predictors.n = 236 for final analysis; margin of error 5.38%). Most survey respondents were female (73.2%), white (90.7%), non-Hispanic (97.0%), in practice <20 years (69.0%), FM clinicians (86.0%), and practicing in the Midwest (88.1%).Clinician ranking of factors that influence their cervical cancer screening practices “very much”  included practice guidelines (97.0%), clinical experience (37.1%), patient preference (22.8%), and patient HPV vaccine status (17.2%). Among those surveyed, 34.8% were aware of the USPSTF guidelines, 2.5% with ACS guidelines only, 41.5% with both guidelines, and 21.2% were not familiar with either guideline .Among the survey respondents, 34.5% reported prior use of primary HPV testing in their clinical practice. The foremost reason for nonuse among the 65.5% of clinicians with no prior use of primary HPV testing was the perception that it is not standard practice at their clinic (68.9%). Only 9.3% reported personal discomfort with the test option and 1.3% expressed that their patients would not be comfortable with the option. Among the 20.5% who selected the option of “other” with a free text box available, we grouped the answers into identified themes that included lack of awareness of national guidelines, concern about evidence supporting primary HPV testing, and not knowing how to order the test in the electronic medical record.Clinician awareness of the concept of patient self-collection of a vaginal sample for HPV testing was reported by 42.8% of survey respondents.When asked to select the three most important test characteristics for patient self-collection, clinicians selected patient ability to obtain an adequate sample (87.7%), test sensitivity (82.6%), and patient acceptability (47.5%). The most common concern about patient self-collection for HPV testing was the missed opportunity to address other health issues (64.3%) followed by concern that women would not return for other care (11.5%). A small number of clinicians were of the opinion that only the provider should perform cervical cancer screening (6.4%) and 17.8% of survey respondents expressed no concern about patient self-collection.p = 0.048) and familiarity with guidelines (p = 0.0001). We observed a high level of support for the three screening scenarios presented: 88.9% of survey respondents were supportive of clinician-collected primary HPV testing; 81.8% were supportive of patient-collected primary HPV testing for women overdue or not previously screened; and 86.0% were supportive of patient-collected primary HPV testing for women previously adherent to screening.Results of bivariate analysis for associations between clinician characteristics and prior use of primary HPV testing, and support for clinician and patient-collected primary HPV testing for cervical cancer are presented in p = 0.03). IM clinicians were universally supportive (100.0%) compared with FM clinicians . Higher levels of support for clinician-collected primary HPV testing were also observed among those who were aware of the USPSTF and/or ACS guidelines (94.1%) compared to those who were not familiar with the guidelines .However, specific clinician characteristics were associated with a greater likelihood of support for clinician-collected primary HPV testing. An increase in practice years was associated with higher levels of support (p = 0.013). No significant differences were observed by other clinician characteristics. Clinician support of patient-collected primary HPV testing in women historically adherent to screening was only associated with type of clinician, with higher support observed among physicians/residents (90.3%) than APPs .Clinician support of patient-collected primary HPV testing in women never screened or overdue for screening was significantly higher among male clinicians (92.1%) compared with female clinicians  prior use of primary HPV testing in practice, (2) support for clinician-collected primary HPV testing, (3) support for patient-collected primary HPV testing for women never screened or underscreened, and (4) support for patient-collected primary HPV testing for women historically adherent to screening. Our multivariable models included clinician type, influence of practice guidelines, and guideline familiarity as predictors .Compared with clinicians familiar with the USPSTF and ACS cervical cancer screening guidelines (referent), those unfamiliar with the guidelines were significantly less likely to report prior use of primary HPV testing in their practices [adjusted OR 0.10 (0.03–0.32)] and significantly less likely to support clinician-collected primary HPV testing for cervical cancer screening [adjusted OR 0.16 (0.07–0.37)].There were no significant predictors identified for clinician support of patient-collected primary HPV testing for cervical cancer screening among women overdue for screening or never screened. APP primary care providers were less likely to support patient-collected primary HPV testing for cervical cancer screening among women with past adherence to screening [adjusted OR 0.42 ] compared with physicians and residents (referent).21 Our results also revealed high levels of support for both clinician-collected and patient-collected HPV testing. The observed discordance between prior use of primary HPV testing in practice compared with reported guideline awareness and support illustrates the challenge of implementing practice change in real-world clinical settings.Among clinicians responding to our survey study, use of primary HPV testing in clinical practice was low, despite high levels of awareness and reported influence of relevant national guidelines. Our results were generally consistent with results of a survey of physicians conducted 3 months after the ASCCP/SGO 2015 interim guidance publication on primary HPV testing where 40.8% of physicians reported routine use of primary HPV screening.®); the addition of this metric may improve interest in and uptake of primary HPV testing in clinical practice as an HPV test alone will “count” toward health care systems quality metrics.24In 2020, primary HPV screening was included as an acceptable performance measure of cervical cancer screening in the Healthcare Effectiveness Data and Information Set (HEDISThe most frequently reported reason for no prior use of primary HPV testing among the clinician survey respondents in our study was their perception that it is not standard practice at their clinic. Other identified barriers included not realizing the test was available or how to order it, lack of awareness of national guidelines or of the evidence supporting primary HPV testing, as well as provider and perceived patient discomfort with the test option.25Educational interventions could be developed to target these specific barriers, although normalizing primary HPV screening as a standard practice option would likely take greater effort. A recent qualitative study from the Kaiser Permanente Southern California health system noted similar clinician concerns about both the evidence for transitioning to primary HPV testing and the test option not being standard practice in other community clinics.25Additional barriers that were not identified in our study included concerns about increased provider workload associated with anticipated patient questions about primary HPV testing and the need to learn a new algorithm to manage abnormal results. Proposed facilitators to implementing a change to primary HPV screening included development of a brief evidence-based primary HPV test fact sheet and a management flowsheet both directed to clinicians and providing a script for clinicians to address patient concerns.26Beyond clinician support for guideline-based clinician-collected primary HPV tests for screening, understanding clinician support for patient collection as an alternative screening option to address screening disparities will become increasingly important once the FDA approves a patient HPV self-test kit. Efforts are currently underway, with support from the National Cancer Institute's Division of Cancer Prevention, to validate patient self-collected HPV testing as a “noninferior” option to clinician collection and to “formally lay out a pathway for regulatory approval for self-sampling approaches for HPV testing” through the “Last Mile Initiative: Self-sampling for HPV testing to Improve Cervical Cancer Prevention” Trial.In our study, clinician support of patient self-collection of a vaginal HPV swab for primary HPV testing was comparable to support reported for clinician-collected primary HPV testing. The main concern among clinicians in our survey with patient self-collection was the potential for a missed opportunity to address other health issues, which is consistent with previously published research.27 Missed opportunity was reported as a reason to not recommend patient self-collection in a clinician survey at the University of Washington as well, although acceptability of patient self-collection for HPV testing was reported if certain test characteristics were met, including high sensitivity, cost effectiveness, patient acceptability, and ability of patient to obtain an adequate sample, similar to reasons endorsed by clinicians in our survey.22In a qualitative study exploring Canadian stakeholder attitudes toward patient self-collection, clinician concern about lost opportunity to address other health issues was a common theme.Strengths of our study include providing updated data on clinician-reported support for and use of primary HPV testing following endorsement by USPSTF in 2018 and following ACS's recommendation of primary HPV testing as the preferred cervical cancer screening option in 2020. We also identified barriers to primary HPV testing in clinical practice. This information may be used to inform future interventional studies to promote uptake of this preferred screening method. In addition, we provided an update to the knowledge base about support among primary care clinicians for a patient self-collection option, for primary HPV testing.As an inherent limitation of a cross-sectional design, causality cannot be determined by our study results. The survey respondents were primarily white, non-Hispanic, female, FM clinicians in the Midwest and as such, results may not be representative of a different population of clinicians. The response rate was relatively low at 30.9%. In addition, the survey data on primary HPV testing use in clinical practice were based on clinician self-report and not confirmed with patient chart reviews or billing data, which would likely improve accuracy.Despite high levels of clinician awareness and support of guidelines, reported as strongly influential on clinical practice, we observed relatively low use of primary HPV testing as a cervical cancer screening option in the surveyed population. Educational interventions for clinicians should be developed to target identified barriers to the uptake of this evidence-based screening test option in clinical practice.


Objective: This study aimed to describe the risk stratification of squamous cell carcinoma (SCC) and its precursor lesions based on HPV E6/E7 mRNA genotyping.Methods: 10647 hrHPV+ women (mean age 40.8 years), who had concurrent cytology and follow-up biopsy results available between September 2016 and May 2020, met the inclusion criteria and were selected for immediate risk analysis.Results: In this cohort, HPV-16 or 18/45+ women had significantly higher immediate risk of cervical cancer and precancer compared with other genotypes+ women. The relative immediate risk (RIR) of ASC-H+ was 2.0 (95% CI: 1.9-2.4) and SCC was 9.4 (95% CI: 5.5-15.6) for HPV-16 or 18/45+ women when compared with women positive for other 11 genotypes. Among follow-up biopsy cases, the RIR of CIN2+ was 2.7 (95% CI: 3.0-3.7) and SCC was 10.8 (95% CI: 7.2-17.4) for HPV-16 or 18/45+ women than women positive for other genotypes. Similarly, when compared with women positive for other genotypes, the RIR of CIN2+ was 2.9 (95% CI: 2.7-4.6) and SCC was 13.8 (95% CI: 3.0-66.2) for HPV-16 or 18/45+ women with ASC-US, and RIR of CIN2+ was 3.3 (95% CI: 3.1-4.6) and SCC was 22.3 (95% CI: 2.8-176.8) for HPV-16 or 18/45+ women with NILM.Conclusions: This study supports that hrHPV mRNA genotyping can be an effective risk stratification tool to identify individual at higher risk for cervical cancer or precancer, and provides important evidences for the future modifications for current China cervical cancer screening guidelines. The vast majority of cervical cancer cases are associated with infection by high risk human papillomavirus (hrHPV), the most common viral infection of the reproductive tract worldwide The incidence and mortality of cervical cancer have largely decreased due to the implementation of preventive cervical cancer screening programs. However, there is still ongoing debate about the best model for routine cervical cancer screening. Consensus guidelines for management of cervical dysplasia in the screening setting have not yet been reached to accommodate the three most widely available screening strategies: primary HPV testing, co-testing with HPV testing and cervical cytology, and cervical cytology The hrHPV randomly integrates into the host genome through a process that includes the disruption of some part of E2 gene which in turn causes the overexpression of the E6 and E7 proteins The aim of this study is to describe the risk stratification of squamous cell carcinoma (SCC) and its precursor lesions in this southern Chinese female population based on HPV genotyping by the Aptima human papillomavirus (AHPV) assay. This test modality was performed on patients referred from routine screening; these referred patients underwent cytological, AHPV assay and biopsy and/or curettage examination. Our study is, to our knowledge and so far, the largest single center this type study in China.This study was approved by the Zhejiang University School of Medicine Women's Hospital Institutional Review Board. A retrospective, computer-based search in the clinical information system database at the Zhejiang University School of Medicine Women's Hospital was performed to identify cases that underwent the AHPV assay between September 2016 to May 2020. As one of the biggest women hospitals in China, Women's Hospital provides care of over 1,500,000 outpatients & 77,000 inpatients annually. Women's hospital is also a cervical cancer screen center of Zhejiang province, one of the most developed and populated provinces of China. Patients included in current study represent women population of an east coast province of southern China who underwent routine clinical cervical cancer screening, with a mixture of urban and rural women population. As shown in Fig A single exfoliated cervical specimen was collected from each participant using a routinely available collection device, which was then rinsed immediately into the ThinPrep  container for AHPV and the liquid-based cytology (LBC) assay. Cytology slides were produced automatically by Thin Prep 2000 . The LBC slides were classified according to the 2014 Bethesda System (TBS) into the following categories: 1) negative for intraepithelial lesion or malignancy (NILM); 2) atypical squamous cells of unknown significance (ASC-US); 3) low-grade squamous intraepithelial lesions (LSIL); 4) atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H); 5) high-grade squamous intraepithelial lesions (HSIL); 6) squamous cell carcinoma (SCC). ASC-H+ was defined as ASC-H or higher (including HSIL and SCC).Residual LBC samples were processed for the AHPV assay, according to the manufacturer's specifications. The AHPV and AHPV-GT  were performed using an automated Panther System . The E6/E7 oncogenic mRNA, which is associated with 14 hrHPV genotypes , was detected by the AHPV. AHPV+ samples were reflex-tested with the AHPV-GT, which can detect the HPVE6/E7 mRNA in hrHPV genotypes 16 and 18/45 or both. AHPV-GT-negative meant the other 11 hrHPV genotypes were positive. Patients who had indeterminate results or residual samples with quantities insufficient for hrHPV assay were excluded from the current study.Histologic correlation results including cervical biopsy and ECC performed within 6 months of the Pap and AHPV assay were included in this study. Histologic results were categorized into three general groups: 1) benign, 2) low-grade cervical lesion (CIN1), and 3) high-grade cervical lesion (CIN2+), defined as CIN2 or higher (CIN3 and SCC). Histopathologic diagnoses were rendered by subspecialized gynecologic pathologists. Cases initially diagnosed as CIN2/3 were confirmed by a second reviewing pathologist for quality assurance purposes. Immunohistochemical staining with p16 and Ki-67 was also liberally used to support the CIN2/3 diagnoses. In patients with more than one tissue sample, the highest grade diagnosis was recorded To analyze the risk of ASC-H+ in cytology specimens, cytology results of ASC-H, HSIL, and SCC were combined into a single “high-grade” category. Meanwhile, NILM, ASC-US and LSIL were combined into a single “non-high-grade” category. The cases were categorized according to the HPV genotypes. Similarly, cytology diagnoses were combined into non-SCC and SCC categories. The two-tailed chi-square test was used to compare the prevalence of “high-grade” lesions or SCC among HPV genotype groups.To analyze the risk of CIN2+ lesions in biopsy specimens, histologic results of CIN2, CIN3 and SCC were combined into a single “high-grade” category, while normal and CIN1 were combined into a single “non-high-grade” category. The cases were categorized according to the HPV genotypes. Similarly, diagnoses were combined into non-SCC and SCC categories. The two-tailed chi-square test was used to compare the prevalence of “high-grade” lesions or SCC among HPV genotype groups. The same strategy was used to analyze the risk of “high-grade” lesions in follow-up biopsies from patients with cytology diagnoses of ASC-US. Statistical analyses were performed using JMP 11.2.0 . A significance level of 0.05 was used.Detailed analysis is included in Table When further analyzed along the genotypes, genotype-specific risk stratification of ASC-H+ cytology was observed. 17.5% HPV-16+ women were diagnosed as ASC-H/HSIL and 2.7% as SCC, while 7.7% and 0.8% HPV-18/45+ women and 8.3% and 0.2% other genotype+ women were diagnosed as ASC-H/HSIL and SCC respectively. In this cohort, when compared to women with infection by other genotype groups, HPV-16+ women had significantly higher immediate risk of ASC-H+  and SCC . In addition, HPV-18/45+ women in this cohort showed significantly higher immediate risk of SCC than women positive for other 11 genotypes (p=0.0035). The relative immediate risk (RIR) of ASC-H+ was 2.4 (95% CI: 2.4-3.1) and SCC was 11.5 (95% CI: 6.9-20.1) for HPV-16+ women when compared with women positive for other 11 genotypes. Together RIR of ASC-H+ was 2.0 (95% CI: 1.9-2.4) and SCC was 9.4 (95% CI: 5.5-15.6) for HPV-16 or 18/45+ women when compared with women positive for other 11 genotypes.Despite the relatively low prevalence among hrHPV+ cytology cases (19.1%), HPV-16 accounted for 33.6% of subsequent HSIL and 68.8% of SCC. HPV-18/45 accounted for 6.3% of ASC-H/HSIL and 8.8% of SCC. Meanwhile, the other 11 genotypes accounted for 59.7% ASC-H/HSIL and 22.5 % of SCC.Detailed analysis is included in Table Despite the relatively low prevalence among hrHPV+ cases (19.1%), HPV-16 accounted for 41.5% of HSIL and 69.8% of SCC. HPV-18/45 accounted for 5.6% of HSIL and 10.1 % of SCC and other 11 genotypes accounted for 51.5% HSIL and 19.4% of SCC.Detailed analysis is included in Table Despite the relatively low prevalence in hrHPV+ women with ASC-US (14.7%), HPV-16 accounted for 38.4% of HSIL and 60% of SCC in follow-up biopsies. HPV-18/45 and other 11 genotypes accounted for 6.1% and 53.0% of CIN2+ lesion respectively, while both genotype groups accounted for 20% of all SCC, respectively. Although there was no significant difference in immediate risk of CIN2+ lesions between HPV-18/45 and other 11 genotypes (p=0.28), the immediate risk of SCC in follow-up biopsies was significantly higher in HPV-18/45+ women than other 11 genotypes positive women (p=0.004). The RIR of CIN2+ was 3.8 (95% CI: 3.8-6.8) and SCC was 15.7 (95% CI: 3.2-79.5) for HPV-16+ women with ASC-US when compared with women positive for other 11 genotypes. Together RIR of CIN2+ was 2.9 (95% CI: 2.7-4.6) and SCC was 13.8 (95% CI: 3.0-66.2) for HPV-16 or 18/45+ women when compared with women positive for other 11 genotypes.Detailed analysis is included in Table Despite the relatively low prevalence in women hrHPV+ with NILM (19.0%), HPV-16 accounted for 47.5% of HSIL and 80% of SCC in follow-up biopsies. HPV-18/45 accounted for 8.4% of CIN2+ and 10% of SCC and other genotypes accounted for 42.9% HSIL and 10% of SCC in follow-up biopsies.Although the immediate risk of CIN2+ and SCC in hrHPV+ women with NILM was significantly lower than hrHPV+ women with ASC-US cytology , there was still a significant immediate risk of CIN2+ lesion in women who were hrHPV+ with NILM (7.7%), especially among HPV-16+ women (19.4%). The RIR of CIN2+ was 4.3 (95% CI: 4.1-6.2) and SCC was 29.9 (95% CI: 3.8-240.6) for HPV-16+ women when compared with women positive for other 11 genotypes. Together RIR of CIN2+ was 3.3 (95% CI: 3.1-4.6) and SCC was 22.3 (95% CI: 2.8-176.8) for HPV-16 or 18/45+ women when compared with women positive for other 11 genotypes.The prevalence of HPV infection and genotype-specific distribution vary greatly among nations In hrHPV+ cytology cases, genotype-specific risk stratification of ASC-H+ cytology was observed in 17.5% of HPV-16+ women diagnosed as ASC-H or HSIL and 2.7% as SCC, while 7.7% and 0.8% HPV-18/45+ women and 8.3% and 0.2% other 11 genotype+ women were diagnosed as ASC-H or HSIL and SCC, respectively. HPV-16+ women had a significantly higher immediate risk of ASC-H+ and SCC than women with infection by the other 11 genotype groups. Despite the relatively low prevalence, HPV-16 and 18/45 accounted for 40% of all ASC-H and HSIL cases, and 77.5% of all SCC cases with HPV-16 alone accounting for 69.8% of all SCC cases. Our data is comparable to that of a Danish study which showed an increased prevalence of HPV-16 and 18 in more severely abnormal cytology findings, and implemented HPV-16 as the genotype most frequently associated with SCC (61.6%) Similar risk stratification was observed in hrHPV+ biopsy cases, such that HPV-16 or 18/45+ women have significantly higher immediate risk of CIN2+ and SCC than women infected with other high-risk genotypes. In addition, HPV-16 and 18/45 accounted for 47.1% of all CIN2+, and 79.8% of all SCC with HPV-16 alone accounting for 69.8% of all SCC. Thus, we are providing further evidence that persistent hrHPV infection is the primary cause of high-grade cervical disease, and persistent infection with HPV-16 and 18/45 pose higher risk for CIN2+ and SCC compared to other high-risk genotypes A pooled hrHPV assay has been routinely used worldwide to stratify risks in women with ASC-US The hrHPV-positive, cytology-negative (NILM) category has been a special challenge for patient management ever since cytology and HPV co-assay was approved by the Food and Drug Administration (FDA) in 2003 There were several limitations in current study. First, as a tertiary referral center, vast majority of our patients got their follow-up and/or treatment at lower-level regional hospital after initial diagnosis. Therefore, we were not able to collect complete long-term follow-up information for most of patients involved in this study. Thus, our study only provided a general assessment of the immediate risk of SCC and its precursor lesions by HPV genotypes in this southern Chinese women population. Future large studies that include hrHPV+ women with sufficient and long-term follow-up information to validate the cervical cancer risk stratification results within this population. However, due to still lack of national/or regional Cervical Cancer Screening Registration Program, the long-term risk analysis in Chinese population is yet to be conducted. This further emphasizes the urgency of establishing such program in China. Second, those cases with abnormal glandular lesions such as ADC and AIS were excluded from this study because the natural history and underlying mechanism of ADC and AIS differ from those of SCC and its precursor lesions. The relationship between specific HPV genotyping and abnormal glandular lesions will be addressed separately in a future study. But to specifically address the risk stratification of SCC and its precursor lesions based on HPV genotyping, the large volume of included cases will offer higher statistical power.There are limited large scale studies on HPV genotype-based cervical cancer risk stratification in the Chinese female population


OBJECTIVES/GOALS: To determine if current U.S. HPV vaccination rates have decreased dysplasia prevalence enough to decrease the positive predictive value (PPV) of abnormal cervical cytology. METHODS/STUDY POPULATION: This retrospective cohort study comprised a chart review of all patients 21-35 years of age who had at least 1 Pap test result within MHealth/Fairview 2016-2018. HPV vaccination data, cervical cancer screening data and dysplasia results were abstracted. Vaccinated was defined as receiving at least 1 dose of HPV vaccine, with subgroup analyses performed for those completing vaccination per ACIP guidelines and by age of initiation dichotomized as 21+ years versus <21 years. RESULTS/ANTICIPATED RESULTS: 49,764 patients meeting study criteria were identified. Among the entire study population, 10% had abnormal cytology results during the study period. Among the 4,928 patients with abnormal cytology, PPV for CIN2+ was lower among vaccinated individuals . Among vaccinated individuals, PPV was lower among those completing vaccination  and among those initiating vaccination at <21 years of age . DISCUSSION/SIGNIFICANCE OF IMPACT: Among a population with low HPV vaccine coverage, the decrease in dysplasia prevalence among vaccinated individuals is resulting in a subsequent decrease in PPV of cervical cytology, particularly in those initiating vaccination prior to 21 years of age and among those completing the series. Confirmation of these results will call for changes in screening strategies for vaccinated individuals. CONFLICT OF INTEREST DESCRIPTION: Acelity: Industry grant for an investigator-initiated industry-sponsored clinical trial. Tesaro: Site PI for industry-sponsored clinical trial. NOTE: Funding from the industries above are unrelated to the research presented in the abstract.


HPV vaccination protects against virus that may cause cervical cancer. Opportunistic HPV vaccination  has been available in Norway since the first HPV vaccine was licensed in 2006. A routine HPV vaccination program targeting 12-year-old girls was introduced in 2009. A delayed catch-up vaccination program was initiated in 2016, offering HPV vaccination free-of-charge to women born in 1991 and later who had not previously been vaccinated in the routine program. The aim of this study was to assess sociodemographic correlates of opportunistic and catch-up HPV vaccine uptake among women in Norway. We found inequalities in both self-paid opportunistic and free-of-charge catch-up HPV vaccine uptake among adolescents and adult women, with particularly low uptake among women with two immigrant parents and among women with a low household income.Achieving equity in human papillomavirus (HPV) vaccination has high priority. In this nationwide registry-based study, we aimed to investigate sociodemographic correlates of HPV vaccine uptake among women who were vaccinated opportunistically at their own initiative and cost during October 2006–June 2018, and among women who were vaccinated free-of-charge in a catch-up vaccination program during November 2016–June 2018. For 840,328 female residents born in Norway between 1975 and 1996, we retrieved HPV vaccination and sociodemographic data from national registries. We used separate models to analyze the sociodemographic correlates of the initiation and completion of HPV vaccination in opportunistic and catch-up vaccination settings. Overall initiation rate for opportunistic HPV vaccination was 2.2%. Uptake increased consistently with birth year, maternal education level, and household income. Having two immigrant parents or a mother working in a lower prestige occupation was strongly associated with low opportunistic vaccination uptake. Similar but weaker inequities were observed in catch-up HPV vaccination. Initiation rate during the first 20 months of the catch-up program was 46.2%. Completion rate was 72.1% and 73.0% for opportunistic or catch-up vaccination, respectively, with small inequities. In conclusion, HPV vaccine uptake was strongly associated with sociodemographic background both in opportunistic and catch-up vaccination settings, with particularly low uptake associated with having two immigrant parents and low household income.  Human papillomavirus (HPV) has a predilection for infecting cutaneous and mucosal epithelial cells and subsequently causes almost all cervical cancer and a substantial fraction of other anogenital and oropharyngeal cancers ,2. It isHPV vaccines were developed against different HPV types, with a bivalent (2v) vaccine providing protection against HPV16, 18, a quadrivalent (4v) vaccine against HPV6, 11, 16, 18 and a nonavalent (9v) vaccine against HPV6, 11, 16, 18, 31, 33, 45, 52, 58. All HPV vaccines have proven to be safe, highly immunogenic, and effective against vaccine-type HPV infection and high-grade cervical lesions in clinical trials [Countries that have achieved high vaccination coverage have also observed 73–85% decline in vaccine-type HPV prevalence, and declines of 41–57% in high-grade cervical lesions among young women less than 10 years after implementation of HPV vaccination . HoweverSociodemographic factors such as education level, socioeconomic status, beliefs, and immigration status may be associated with attitudes toward general health, vaccination in general as well as HPV vaccination, and thereby HPV vaccine uptake ,13. UptaThe first HPV vaccine was licensed in Norway in October 2006, and self-paid opportunistic vaccination with a recommended three-dose schedule has since been available. Opportunistic vaccination happens at a citizen’s request to a physician and is thus not part of a vaccination program. In 2009, free of charge HPV vaccination became part of the Norwegian childhood vaccination program, starting off with routine HPV vaccination administered at school to girls in the 7th grade . RegularWe performed a nationwide registry-based study to investigate sociodemographic correlates of HPV vaccination in self-paid opportunistic and free-of-charge catch-up vaccination settings among women in Norway, aiming to identify barriers to achieving the targets set by the WHO’s global strategy to accelerate the elimination of cervical cancer as a public health problem.All data in this population-based study were extracted from nationwide registries, which were linked on an individual level via the unique personal identification number (PIN) that is given to each Norwegian citizen at birth or immigration . We focuFrom Statistics Norway, we extracted information for each cohort member on parental country of birth, maternal education level, maternal occupation, and household income after tax. We used socioeconomic data from the calendar year when the subject became eligible for HPV vaccination, which was defined as the last occurrence among the year of the ninth birthday (the youngest recommended age for HPV vaccination in Norway), 2006 (the year for licensure of the first HPV vaccine), or the year of immigration to Norway.Information on HPV vaccination for each cohort member was obtained for the period October 2006–June 2018. We extracted dates of vaccination and prescription for each dose from the Norwegian Immunization Registry (SYSVAK) and the Prescription Registry, respectively, for all HPV vaccines available in Norway during this period. We used data from SYSVAK when available, and supplemented with data from the Prescription Registry if women were registered with less than three doses of the same vaccine type in SYSVAK and there were additional data from the Prescription Registry.We defined opportunistic vaccination as any vaccination happening outside the organized routine or catch-up program. Opportunistically vaccinated women have to pay for the vaccination themselves, which currently has a cost of €300–400 for three doses . Prices have been similarly high throughout the study period, although it varies some by calendar year and vaccine type. The entire study cohort was eligible for opportunistic HPV vaccination. Women born from 1975 to 1990 were not age-eligible for catch-up vaccination and any HPV vaccination administered during the follow-up period of October 2006–June 2018 was considered opportunistic for these birth cohorts. Women born from 1991 to 1996 contributed to the opportunistic vaccination cohort until the start of the catch-up program , as seen in Women who did not receive any dose of HPV vaccine during follow-up were classified as unvaccinated. Women eligible for opportunistic vaccination who received at least one dose of any HPV vaccine were classified as having initiated opportunistic vaccination, and women eligible for catch-up vaccination who received at least one dose of the 2v vaccine were classified as having initiated catch-up vaccination. Women who received at least three doses of the same HPV vaccine within one year were classified as having completed HPV vaccination . Completp-values less than 0.05 were considered statistically significant.Opportunistic and catch-up vaccination were assessed in separate models. We used Cox regression models and reported hazard ratios (HR) and 95% confidence intervals (CI) in the analyses of HPV vaccination initiation. We used logistic regression models and reported odds ratios (ORs) and 95% CI in the analyses of HPV vaccination completion among women who initiated HPV vaccination. We performed unadjusted univariate analyses of each independent variable as well as adjusted multivariate analyses with several of the independent variables included in the same model. The same variables with the same categories were addressed for all outcomes. For ordinal variables, we chose the lowest category as the reference level, while for nominal variables, we generally chose the category with the highest number of women as the reference category. Individuals with missing values for a sociodemographic variable were excluded from models including this variable, thus sample size differed between models. Due to the high proportion of missing values for maternal education and maternal occupation resulting from relatively low completeness for these variables at Statistics Norway, we did not include these variables in the adjusted models. Statistical analysis was performed with R Studio version 3.6.1. All tests were two-sided, and A total of 840,328 women born in the period 1975–1996 and resident in Norway at any time during the period October 2006 to June 2018 were identified. We excluded 438 women with uncertain immigration/emigration status and 639 women with uncertain vaccination data, resulting in a cohort of 839,251 women eligible for analyses .Among the 839,251 women eligible for opportunistic HPV vaccination, 1476, 16,976 and 929 women had at least one dose of the 2v, 4v, or 9v vaccine, respectively, of which a total of 18,699 women had at least one dose of any kind of vaccine. The initiation rate was thus 2.2% in the opportunistic setting. Among the 201,326 women eligible for catch-up vaccination during the study period, 92,913 had at least one dose of the 2v vaccine, resulting in an initiation rate of 46.2% during the first 20 months of the catch-up program (the program continued after the end of follow-up of the present study). The median age at initiation of HPV vaccination was 21.3 years (interquartile range: 16.4–27.6 years) in the opportunistic setting, and 23.3 years (interquartile range: 21.8–24.8 years) in the catch-up setting. HPV vaccination completion rate among women who had initiated vaccination was 72.1% and 73.0% for opportunistic and catch-up HPV vaccination, respectively.p < 0.001). The initiation rate also differed significantly by parental country of birth. Women with two immigrant parents were far less likely to initiate opportunistic HPV vaccination compared to women with two Norwegian-born parents, with initiation rates of 0.6% and 2.9%, respectively . However, women with one foreign-born and one Norwegian-born parent had the highest uptake at 3.8% .There were considerable differences in the initiation rate of opportunistic HPV vaccination for most of the sociodemographic variables . For yeap < 0.001). Maternal occupation was also associated with opportunistic HPV vaccine initiation. Compared to women with mothers in higher prestige occupations, women with mothers in lower prestige occupations had a lower opportunistic initiation rate . A consistently positive association was observed for household income, with the initiation rate increasing from 1.3% in the lowest income bracket to 6.9% in the highest income bracket . There were small but significant differences in opportunistic HPV vaccine uptake between geographical regions, ranging from 1.8% in Mid-Norway to 2.8% in West-Norway . Women with two immigrant parents also had a lower likelihood of completing opportunistic vaccination compared to women with two Norwegian-born parents . Unlike the corresponding initiation analyses, a progressively positive association was not observed between opportunistic vaccination completion and maternal education or household income, and there was no association with maternal occupation.The analyses addressing completion of opportunistic HPV vaccination  showed sp < 0.001). A total of 45.1% of women with one Norwegian-born and one foreign-born parent initiated catch-up vaccination compared to 53.9% of those with two Norwegian-born parents . Women with mothers with the lowest education level had a relatively low catch-up initiation rate (40.4%), especially when compared to women with the most highly educated mothers . The highest catch-up initiation rate was observed among women with mothers in higher prestige occupations (59.5%), which was nearly 10 percentage points higher than among women with mothers working in lower prestige occupations . Women in households with the lowest income had a very low catch-up initiation rate (29.0%) in contrast to women in households with the highest income .The overall patterns between sociodemographic status and the initiation of catch-up HPV vaccination  were simAmong women who initiated catch-up HPV vaccination, there was little difference in completion across the categories of each variable. However, most patterns observed for the initiation of catch-up vaccination were also observed for completion, although the absolute and relative effect sizes were smaller .This nationwide population-based cohort study examined sociodemographic status in relation to the initiation and completion of opportunistic and catch-up HPV vaccination in Norway. We found a very low initiation rate (2.2%) and a suboptimal completion rate (72.1%) of opportunistic HPV vaccination between 2006 and 2018 among Norwegian women born 1975–1996. The catch-up program was not yet completed by the end of follow-up of the present study, hence the final uptake rate for the entire catch-up program is higher than reported here. Several sociodemographic characteristics were strongly associated with uptake of opportunistic HPV vaccination with the lowest initiation and completion rates observed among women in older birth cohorts, women with two immigrant parents, women with mothers with the lowest education, and women living in households with the lowest income. A similar pattern was observed for HPV catch-up vaccination, a setting with a much higher uptake rate.We observed that women in younger birth cohorts were more likely to initiate and complete vaccination, particularly in the opportunistic setting. HPV vaccination at a young age is important because HPV vaccine efficacy is low among those previously exposed to HPV infection ,21,22. TCompletion of the vaccination series was suboptimal in both vaccination settings investigated, which is likely to further reduce the effectiveness of HPV vaccination in the cohorts studied here. Raised awareness toward completing the vaccine series among adolescent and adult women seems warranted. Opportunistic and catch-up vaccination in Norway requires attendance at a general practitioner, pharmacy, or a public health clinic, which in part may explain why the completion rate is lower than in the routine school-based setting  where vaParental country of birth was one of the strongest predictors of both initiation and completion of opportunistic and catch-up HPV vaccination. We found that women with two immigrant parents were far less likely to initiate HPV vaccination compared to women with two Norwegian-born parents. These results are in line with findings of subsidized opportunistic vaccination in Sweden  and catcHousehold income was strongly correlated with HPV vaccine uptake in both vaccination settings. Financial status has also been shown to be important for opportunistic HPV vaccine uptake in China , and SweWe noted some regional differences in both opportunistic and catch-up HPV vaccine uptake. We do not know what caused these differences, but one possibility is vaccine accessibility. The regions differ in population density, which could impact on the effort and cost of reaching a vaccine provider. Moreover, vaccine delivery in the childhood vaccination program is administered by local municipality health services  and the Previous studies on the associations between sociodemographic characteristics and HPV vaccine uptake have mainly focused on uptake among children and young adults ,36,39. TSeveral of the sociodemographic variables included in the present study are correlated with each other, as indicated by the observation that estimates of the same variable sometimes differed between unadjusted and adjusted models. However, most effects observed in the unadjusted models were also significant after adjustment, indicating that the variables also contributed independently to the association with HPV vaccine uptake.All data used in this study were extracted from nationwide registers, which ensures objective data and avoids selection and response bias. Moreover, this study had a large sample size and high power to detect differences in HPV vaccine uptake. However, the analyses presented here do not address causal relationships and cannot identify the factors that motivate the decision whether or not to have the HPV vaccine. Moreover, although we presented adjusted analyses, residual confounding is likely. Further limitations of this study are the high proportion of missing data for maternal education and occupation, which limits the inference that can be drawn regarding these variables, and the fact that we do not have access to data of HPV vaccination that may have happened outside Norway. Finally, the catch-up program was not entirely completed by the end of follow-up of the present study, thus the catch-up results presented do not constitute the entire catch-up program.Self-paid opportunistic HPV vaccination among Norwegian women is characterized by a very low initiation rate, a suboptimal completion rate, and a high age at vaccination, with the lowest uptake among women of low socioeconomic status and women with two immigrant parents. Thus, the opportunistic HPV vaccination setting is inefficient from a public health perspective and does not promote equity in access to preventive health care. Providing free-of-charge vaccination to women in their 20s through a catch-up program greatly increases the initiation rate compared to opportunistic vaccination, but delayed catch-up vaccination also suffers from inequalities and suboptimal completion. Targeted campaigns in catch-up vaccination programs toward immigrants and socially deprived groups could mitigate the disparities observed in the present study.


Background: Australian adolescents are routinely offered HPV and dTpa  vaccines simultaneously in the secondary school vaccination program. We identified schools where HPV initiation was lower than dTpa coverage and associated school-level factors across three states. Methods: HPV vaccination initiation rates and dTpa vaccination coverage in 2016 were calculated using vaccine databases and school enrolment data. A multivariate analysis assessed sociodemographic and school-level factors associated with HPV initiation being >5% absolute lower than dTpa coverage. Results: Of 1280 schools included, the median school-level HPV initiation rate was 85% (interquartile range (IQR):75–90%) and the median dTpa coverage was 86% (IQR:75–92%). Nearly a quarter (24%) of all schools had HPV vaccination initiation >5% lower than dTpa coverage and 11 % had >10% difference. School-level factors independently associated with >5% difference were remote schools  and schools in major cities , small schools , higher socioeconomic advantage , and lower proportions of Language-background-other-than-English . Conclusion: The results identified a quarter of schools had lower HPV than dTpa initiation coverage, which may indicate HPV vaccine hesitancy, and the difference was more likely in socioeconomically advantaged schools. As hesitancy is context specific, it is important to understand the potential drivers of hesitancy and future research needs to understand the reasons driving differential uptake. Human papillomavirus (HPV) is the most common sexually transmissible infection (STI) globally and is associated with significant morbidity and mortality due to cervical and other cancers and genital warts, with 50–80% of the general population acquiring HPV infection with one or more types at some point in their life . InfectiThree vaccines that protect against oncogenic types of HPV have been, or are currently, licensed in most countries: a bivalent vaccine; a quadrivalent vaccine , and a nAustralia was the first country to implement a national school-based HPV vaccination program. Since its introduction, it has achieved high coverage of HPV vaccination, reaching just over 80% of 15-year-olds in 2017 for the three-dose course . VaccineOne objective marker of hesitancy towards the HPV vaccination specifically  is if parents refuse the HPV vaccine but consent to other adolescent vaccinations offered at the same time. In Australia we have a unique opportunity to measure this, as HPV vaccine is co-administered in schools with the diphtheria tetanus pertussis acellular (dTpa) vaccine. The dTpa vaccine was implemented as a booster for adolescents in Australia in 2004, building on a long-standing childhood vaccination program underway since 1986 . HPV vacA previous ecological study from the United Kingdom, found differential coverage between the HPV vaccine and the meningococcal A, C, W and Y (MenACWY) vaccine . HoweverIn this study, we aimed to estimate the school-level coverage of dose one of the HPV vaccine and the dTpa booster, in three Australian states, and identify school-level correlates associated with lower relative coverage of the HPV vaccine. We conducted an ecological analysis of HPV and dTpa vaccine coverage across three Australian states—New South Wales (NSW), Tasmania (TAS) and Western Australia (WA), with the school as the unit of analysis. We included first year secondary school students aged 11–13 years enrolled in all secondary schools that provide education to adolescents from around 11 to 18 years of age in the three states, and only included those in the first year of secondary school, generally aged 11–13 years, and schools for which both year-specific student enrolment numbers, as well as delivered HPV vaccination doses and dTpa doses were available for 2016. The primary outcome for each school was binary, defined by whether the proportion of adolescents in the school who received the first dose of HPV vaccine  in 2016 was more than 5% lower than the proportion who received dTpa in the same year (dTpa coverage), hereafter designated as ‘lower HPV coverage than dTpa’. The denominator for each proportion was the total school enrolments. We chose a difference of 5% or more between HPV and dTpa coverage as it was considered clinically meaningful given the high overall coverage of HPV vaccination in Australia.We obtained data from the following four existing administrative datasets held by state and national statutory bodies to calculate the study outcomes and co-variates. All datasets were at the school or postcode level.1. The National HPV Vaccination Program Register (NHPVR): until 2018, collected details of individual doses of HPV vaccine delivered in Australian schools and general practice/primary health care services as notified to the register as part of the National Immunisation Program (NIP). We obtained vaccination doses given by cohort year and school name. The register did not collect information on dTpa vaccines.2. Jurisdictional health departments: collect individual data on HPV and dTpa doses delivered in schools. We obtained dTpa vaccination doses and school enrolment data for each school grade in which the vaccine program was delivered . HPV doses were not requested, as these were available through the NHPVR. Enrolment data collected from NSW, WA and TAS included graded schools (which denoted school year) for mainstream schools and special education schools. WA also included ungraded ‘special education’ schools (schools that do not place students in a specific year level).3. The Australian Curriculum, Assessment and Reporting Authority (ACARA): collects and reports characteristics of schools and their students . 4. The Australian Bureau of Statistics: is a national statutory body which collects demographic data from Australian residents by a Census every five years , from whWe first merged the datasets above deterministically based on the school name and postcode, and then for those remaining unmatched via probabilistic matching using the STATA reclink command . RemainiWe then conducted descriptive analyses of school-level HPV coverage and dTpa coverage at the school-level for the three jurisdictions. This included calculation of the overall coverage of both vaccines for each school. Across schools this included calculation of means, standard deviations, medians, ranges, and interquartile ranges (IQR). We calculated the proportion of schools where HPV vaccine was lower than dTpa, and the proportion of schools where dTpa was lower than HPV vaccine, and for each categorised the differences as +/− 0%, 0–5%, >5–10% and >10% difference.We conducted univariate and multivariate analysis to identify sociodemographic and school-related factors associated with the primary outcome of ‘lower HPV coverage’ defined as HPV coverage that was at least five percentage points lower than dTpa coverage. Sociodemographic variables included the percent of enrolments with Aboriginal and/or Torres Strait Islander background (referred to hereafter as Indigenous students), the percent of enrolments with a language-background-other-than-English, and the Index of Relative Socio-Economic Disadvantage (SEIFA IRSD) , defined by postcode of the school . School-Variables associated with the primary outcome were first assessed using univariate logistic regression models. The reference categories were selected based on normative groups that have been identified in the literature as not having a tendency towards vaccination hesitancy  ,41,42. Bp-value < 0.10 were included in the initial full multivariable model. Covariates with overall statistical significance of p < 0.05 based on the test for heterogeneity were included in the final reduced models. We present the odds ratios and 95% CIs. We restricted the analysis to schools with a vaccine-eligible enrolment of at least 10 students to minimise the influence of schools with very small numbers. The final multivariable model was also adjusted for a five-level school affiliation variable, which included Independent, Catholic, Government schools and jurisdiction. However, to maintain anonymity as requested by stakeholders in the education sector, coverage and correlation by school affiliation is not reported publicly but the results were provided to relevant program managers to inform future policy priorities. Variables with a Ethical approval was provided by the Human Research Ethics Committees of the University of New South Wales (HC17632), the Australian National University (2017/516), the University of Tasmania (1320/17), the Aboriginal Health and Medical Research Council of New South Wales (1320/17), the Aboriginal Health Council of Western Australia (818), and the Department of Health of Western Australia (RGS0000000456).Of 1327 schools in the dataset, we excluded 39 schools with no 2016 enrolment data, two not located in a participating jurisdiction, and the remainder because the school name was not available in both the numerator and denominator data to enable matching of the datasets with the NHPVR. An additional six schools were excluded as they did not report on doses of dTpa given, leaving 1280 schools included in the final analysis.n = 674) had lower HPV than dTpa coverage and 32% (n = 410) lower dTpa than HPV coverage , 33% were small schools (enrolment of 11–383 students), 33% were located in areas in the most socioeconomically disadvantaged tertile and 35% had low attendance rates  see . The medcoverage . Of the coverage . In the univariate analysis, sociodemographic factors associated with lower HPV coverage were: schools with a lower proportion of Indigenous student enrolments , schools with a lower proportion of adolescents from non-English language backgrounds  and schools with a higher proportion of adolescents from areas of greatest socioeconomic advantage (OR 2.0 95% CI = 1.4–2.8) . School In the multivariate analysis, sociodemographic factors independently associated with lower HPV coverage were: schools with a lower proportion of Indigenous student enrolments , a lower proportion of adolescents from non-English-language-backgrounds , and a higher proportion of adolescents from areas of greatest socioeconomic advantage . School related factors independently associated lower HPV coverage were: location in remote areas , or major cities ; and small school size  or medium size  . We identified variation in the uptake of HPV and dTpa vaccines in the school-based immunisation program, with HPV coverage at least 5% lower than dTpa coverage in 23% of schools in the three states. To our knowledge this is the first study to compare coverage of these two school-based vaccines in Australia and examine school-level factors associated with differences in their coverage. We found that schools with a higher proportion of adolescents from areas with higher socio-economic advantage and from English-speaking backgrounds were more likely to have lower HPV coverage than dTpa coverage. We also found that the size of the school was an independent predictor, with small- and medium-sized schools more likely to report a greater than 5% difference between HPV dose 1 and dTpa than larger schools. More than 14% of schools had a substantially lower HPV coverage of more than 10%, suggesting the difference is an important contributor to lower uptake at the population level. We also found that in 32% of schools dTpa coverage was lower than HPV, which may potentially be explained by adolescents having received a diphtheria tetanus vaccine previously for tetanus prevention, if a child or adolescent had a recent cut or wound that could have been in contact with soil, or routine travel vaccination. In Australia, children aged <10 years with a tetanus-prone wound are recommended to receive DTPa or a DTPa combination vaccine, and people aged ≥10 years are recommended to receive a booster dose of dT or dTpa if their last dose was more than 5 years ago .Schools in our study were more likely to report a larger difference between dTpa and HPV if they were small or medium sized schools and had enrolment between 11 and 844, in comparison to larger schools in the study. A study from the UK that found differential coverage between the HPV vaccine and the meningococcal A, C, W and Y (MenACWY) vaccine, also identified smalls schools as achieving lower coverage . It is cWe found that several sociodemographic characteristics relating to the school were strongly associated with lower HPV coverage than dTpa coverage, including being located in less disadvantaged areas and a higher proportion of students from English-speaking backgrounds. Studies from the US and Denmark have also found that parents and girls from higher socio-economic areas were more likely to be hesitant about HPV vaccination ,46. The We also found that schools with a very small proportion of Indigenous students enrolled were more likely to have HPV coverage that was lower than dTpa . In a recent analysis we conducted from this same dataset, we found schools with a higher proportion of Indigenous student enrolments were associated with a lower absolute uptake of HPV, both initiation and completion . SchoolsWe identified some school related factors associated with lower HPV coverage than dTpa in our analysis. School size has previously been reported as independently associated with differential uptake of adolescent vaccines, as well as lowest coverage of vaccines compared to larger schools . The assOur study has a few limitations to consider when interpreting the findings. First, we used an ecological approach to identify schools and specific characteristics associated with relatively lower uptake of HPV compared to dTpa. Therefore, our approach does not assess risk factors at the individual level, but rather provides an indication of school-level factors which can inform interventions and future research. The co-variates were based on those routinely available in a range of datasets, and some may have been markers of other risk factors. For example, we measured English language backgrounds rather than more nuanced factors such as ethnicity or cultural or religious background. Also, some variables were only available at the postcode rather than the school level, and in some postcodes, there is considerable variation in the sociodemographic of the population. Third, many of the variables describing school characteristics were highly correlated, which may have led to an inability to resolve confounding and distinguish causally related factors. Fourth, the HPV and dTpa uptake calculation only included vaccinations that could be attributed to a school, which was necessary for the analysis, but may have somewhat under-estimated true vaccine coverage. Lastly, coverage of HPV and dTpa was not obtained from the same data source, but our calculations of HPV coverage from the National HPV Vaccination Program Register is similar to those reported by the jurisdictions separately ,62, so wIn conclusion, our study identified several key sociodemographic characteristics and school related factors that were associated with HPV coverage that is >5% lower than another adolescent vaccine co-administered in the school setting. This is an important finding as it may indicate a degree of hesitancy specifically to the HPV vaccine in some contexts within Australia, which has previously not been identified in the literature. It is important to conduct further research to confirm if hesitancy is contributing to lower HPV vaccine coverage in some schools, and the potential drivers of hesitancy . The res