The Improving Risk Informed HPV Screening (IRIS) Study: Design and Baseline Characteristics.

Background: Cervical cancer screening with high-risk human papillomavirus (HrHPV) testing is being introduced. Most HrHPV infections are transient, requiring triage tests to identify individuals at highest risk for progression to cervical cancer. Head-to-head comparisons of available strategies for screening and triage are needed.

Association of HPV35 with cervical carcinogenesis among women of African ancestry: Evidence of viral-host interaction with implications for disease intervention.

HPV35 has been found in only ∼2% of invasive cervical cancers (ICC) worldwide but up to 10% in Sub-Saharan Africa, warranting further investigation and consideration of impact on preventive strategies. We studied HPV35 and ethnicity, in relation to the known steps in cervical carcinogenesis, using multiple large epidemiologic studies in the U.S.

A Study of Partial Human Papillomavirus Genotyping in Support of the 2019 ASCCP Risk-Based Management Consensus Guidelines.

Introduction: The 2019 ASCCP Risk-Based Management Consensus Guidelines include recommendations for partial human papillomavirus (HPV) genotyping in management of abnormal cervical cancer screening results. The guidelines are based on matching estimates of cervical intraepithelial neoplasia (CIN) 3+ risk to consensus clinical action thresholds. In support of the guidelines, this analysis addresses the risks predicted by individual identification of HPV 16 and HPV 18.

Absolute risks of cervical precancer among women who fulfill exiting guidelines based on HPV and cytology cotesting.

US guidelines recommend that most women older than 65 years cease cervical screening after two consecutive negative cotests (concurrent HPV and cytology tests) in the previous 10 years, with one in the last 5 years. However, this recommendation was based on expert opinion and modeling rather than empirical data on cancer risk. We therefore estimated the 5-year risks of cervical precancer (cervical intraepithelial neoplasia grade 3 or adenocarcinoma in situ [CIN3]) after one, two and three negative cotests among 346,760 women aged 55-64 years undergoing routine cotesting at Kaiser Permanente Northern California (2003-2015).

Role of Screening History in Clinical Meaning and Optimal Management of Positive Cervical Screening Results.

Background: Cervical cancer is caused by persistent human papillomavirus (HPV) infection. US consensus management guidelines for a positive cervical screening result typically focus on the current screening result only. A negative testing history may alter risk of the following positive screening results, caused by a new HPV infection, and therefore its optimal management.

Impact of human papillomavirus vaccination on the clinical meaning of cervical screening results.

Women previously vaccinated against human papillomavirus (HPV) type 16 and 18 are now reaching the age (21 years) at which cervical-cancer screening is recommended in the U.S. The impact of HPV vaccination on risks of cervical precancer following a positive and negative screen among women aged 21-24 years who just started routine cervical screening are not well described.

Automated Cervical Screening and Triage, Based on HPV Testing and Computer-Interpreted Cytology.

Background: State-of-the-art cervical cancer prevention includes human papillomavirus (HPV) vaccination among adolescents and screening/treatment of cervical precancer (CIN3/AIS and, less strictly, CIN2) among adults. HPV testing provides sensitive detection of precancer but, to reduce overtreatment, secondary "triage" is needed to predict women at highest risk. Those with the highest-risk HPV types or abnormal cytology are commonly referred to colposcopy; however, expert cytology services are critically lacking in many regions.

Clinical Outcomes after Conservative Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) in Women Ages 21-39 Years.

Cervical intraepithelial neoplasia grade 2 (CIN2) frequently regresses, is typically slow-growing, and rarely progresses to cancer. Some women forgo immediate treatment, opting for conservative management (heightened surveillance with cytology and colposcopy), to minimize overtreatment and increased risk of obstetric complications; however, there are limited data examining clinical outcomes in these women. We performed a retrospective cohort analysis of younger women diagnosed with initially untreated CIN1/2, CIN2 and CIN2/3 lesions at Kaiser Permanente Northern California between 2003 and 2015.

Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting.

Although guidelines have recommended extended interval cervical screening using concurrent human papillomavirus (HPV) and cytology ("cotesting") for over a decade, little is known about its adoption into routine care. Using longitudinal medical record data (2003-2015) from Kaiser Permanente Northern California (KPNC), which adopted triennial cotesting in 2003, we examined adherence to extended interval screening. We analyzed predictors of screening intervals among 491,588 women undergoing routine screening, categorizing interval length into early (<2.

Challenges in risk estimation using routinely collected clinical data: The example of estimating cervical cancer risks from electronic health-records.

Electronic health-records (EHR) are increasingly used by epidemiologists studying disease following surveillance testing to provide evidence for screening intervals and referral guidelines. Although cost-effective, undiagnosed prevalent disease and interval censoring (in which asymptomatic disease is only observed at the time of testing) raise substantial analytic issues when estimating risk that cannot be addressed using Kaplan-Meier methods. Based on our experience analysing EHR from cervical cancer screening, we previously proposed the logistic-Weibull model to address these issues.

Effect of Several Negative Rounds of Human Papillomavirus and Cytology Co-testing on Safety Against Cervical Cancer: An Observational Cohort Study.

Background: Current U.S. cervical cancer screening and management guidelines do not consider previous screening history, because data on multiple-round human papillomavirus (HPV) and cytology "co-testing" have been unavailable.

Relative Performance of HPV and Cytology Components of Cotesting in Cervical Screening.

Background: The main goal of cervical screening programs is to detect and treat precancer before cancer develops. Human papillomavirus (HPV) testing is more sensitive than cytology for detecting precancer. However, reports of rare HPV-negative, cytology-positive cancers are motivating continued use of both tests (cotesting) despite increased testing costs.

Risks of CIN 2+, CIN 3+, and Cancer by Cytology and Human Papillomavirus Status: The Foundation of Risk-Based Cervical Screening Guidelines.

Objectives: The next round of the American Society for Colposcopy and Cervical Pathology (ASCCP)-sponsored cervical cancer screening and management guidelines will recommend clinical actions based on risk, rather than test-based algorithms. This article gives preliminary risk estimates for the screening setting, showing combinations of the 2 most important predictors, human papillomavirus (HPV) status and cytology result.

Materials And Methods: Among 1,262,713 women aged 25 to 77 years co-tested with HC2 (Qiagen) and cytology at Kaiser Permanente Northern California, we estimated 0-5-year cumulative risk of cervical intraepithelial neoplasia (CIN) 2+, CIN 3+, and cancer for combinations of cytology (negative for intraepithelial lesion or malignancy [NILM], atypical squamous cells of undetermined significance [ASC-US], low-grade squamous intraepithelial lesion [LSIL], atypical squamous cells cannot exclude HSIL [ASC-H], high-grade squamous intraepithelial lesion [HSIL], atypical glandular cells [AGC]) and HPV status.

Why does cervical cancer occur in a state-of-the-art screening program?

Background: The goal of cervical screening is to detect and treat precancers before some become cancer. We wanted to understand why, despite state-of-the-art methods, cervical cancers occured in relationship to programmatic performance at Kaiser Permanente Northern California (KPNC), where >1,000,000 women aged ≥30years have undergone cervical cancer screening by triennial HPV and cytology cotesting since 2003.

Methods: We reviewed clinical histories preceding cervical cancer diagnoses to assign "causes" of cancer.

Assessment of a New Lower-Cost Real-Time PCR Assay for Detection of High-Risk Human Papillomavirus: Useful for Cervical Screening in Limited-Resource Settings?

Inexpensive and easy-to-perform human papillomavirus (HPV) tests are needed for primary cervical cancer screening in lower-resource regions. In a convenience sample of 516 residual exfoliative cervical specimens from the Kaiser Permanente Northern California and U.S.

The population impact of human papillomavirus/cytology cervical cotesting at 3-year intervals: Reduced cervical cancer risk and decreased yield of precancer per screen.

Background: The objective of cervical screening is to detect and treat precancer to prevent cervical cancer mortality and morbidity while minimizing overtreatment of benign human papillomavirus (HPV) infections and related minor abnormalities. HPV/cytology cotesting at extended 5-year intervals currently is a recommended screening strategy in the United States, but the interval extension is controversial. In the current study, the authors examined the impact of a decade of an alternative, 3-year cotesting, on rates of precancer and cancer at Kaiser Permanente Northern California.

Age-stratified 5-year risks of cervical precancer among women with enrollment and newly detected HPV infection.

It is unclear whether a woman's age influences her risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) upon detection of HPV. A large change in risk as women age would influence vaccination and screening policies. Among 972,029 women age 30-64 undergoing screening with Pap and HPV testing (Hybrid Capture 2, Qiagen, Germantown, MD) at Kaiser Permanente Northern California (KPNC), we calculated age-specific 5-year CIN3+ risks among women with HPV infections detected at enrollment, and among women with "newly detected" HPV infections at their second screening visit.

The low risk of precancer after a screening result of human papillomavirus-negative/atypical squamous cells of undetermined significance papanicolaou and implications for clinical management.

Background: Different US practice guidelines have conflicting recommendations for when women should return after a screening result of human papillomavirus (HPV)-negative with an equivocal Papanicolaou (Pap) result of atypical squamous cells of undetermined significance (ASC-US) (ie, return in either 3 or 5 years). One way to determine management is to compare the risk of precancer/cancer after an HPV-negative/ASC-US result with the risks after other negative screening results. For example, if the risk after an HPV-negative/ASC-US result was similar to the risk after a negative Pap test, a 3-year return would be preferred because guidelines agree that women with negative Pap test results should return in 3 years.

Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test.

Primary human papillomavirus (HPV) testing (without concurrent Pap tests) every 3 years is under consideration in the United States as an alternative to the two recommended cervical cancer screening strategies: primary Pap testing every 3 years, or concurrent Pap and HPV testing ("cotesting") every 5 years. Using logistic regression and Weibull survival models, we estimated and compared risks of cancer and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) for the three strategies among 1011092 women aged 30 to 64 years testing HPV-negative and/or Pap-negative in routine screening at Kaiser Permanente Northern California since 2003. All statistical tests were two sided.

Five-year risk of recurrence after treatment of CIN 2, CIN 3, or AIS: performance of HPV and Pap cotesting in posttreatment management.

Objective: After excisional treatment, cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) can recur. It is not clear how many negative posttreatment Pap or cotest results are needed to ensure adequate safety against CIN 2+ before returning to extended retesting intervals.

Methods: We observed 5-year risks of CIN 2+ for 3 follow-up management strategies after treatment (Pap-alone, human papillomavirus [HPV]-alone, and HPV/Pap cotesting) for 3,273 women aged 25 years and older who were treated for CIN 2, CIN 3, or adenocarcinoma in situ (AIS) between 2003 and 2010 at Kaiser Permanente Northern California.

Follow-up testing after colposcopy: five-year risk of CIN 2+ after a colposcopic diagnosis of CIN 1 or less.

Objective: Most women referred for colposcopy are not diagnosed with cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) but, nonetheless, are typically asked to return much sooner than their next routine screening interval in 3 to 5 years. An important question is how many subsequent negative Pap results, or negative Pap and human papillomavirus (HPV) cotest results, are needed before returning to an extended retesting interval.

Methods: We estimated 5-year risks of CIN 2+ for 3 follow-up management strategies after colposcopy (Pap-alone, HPV-alone, and cotesting) for 20,319 women aged 25 years and older screened from 2003 to 2010 at Kaiser Permanente Northern California who were referred for colposcopy but for whom CIN 2+ was not initially diagnosed (i.

Five-year risk of CIN 3+ to guide the management of women aged 21 to 24 years.

Objective: Current US national guidelines recommend beginning screening at age 21 using Pap tests only, with cotesting starting at age 30. To inform the management of Pap test abnormalities among women aged 21 to 24 years, who have extremely low cancer risks, we compared risks of CIN 3+ among women aged 21 to 24 versus 25 to 29 years or 30 to 64 years.

Methods: We estimated 5-year risks of CIN 3+ given different Pap test results, with human papillomavirus (HPV) triage of atypical squamous cells of undetermined significance (ASC-US), among 133,947 women aged 21 to 24 years, compared with 135,382 women aged 25 to 29 years and 965,360 women aged 30 to 64 years, between 2003 and 2010 at Kaiser Permanente Northern California.