BACKGROUND:Cervical intraepithelial neoplasia (CIN) grade 2 (CIN 2) is an equivocal diagnosis of cervical precancer, and appropriate management continues to be debated. OBJECTIVE:To estimate the effect of immediate (by 6 months) versus delayed (after 6 months or no) treatment of CIN 2. DESIGN:Observational emulation of a target trial of immediate versus delayed treatment, using inverse probability weighting (IPW) to adjust for baseline factors. SETTING:Routine cervical screening at Kaiser Permanente Northern California. PATIENTS:12 012 women with CIN 2 found on initial biopsy from 2017 to 2023. INTERVENTION:Immediate treatment (excision by 6 months after initial CIN 2 without interim surveillance by screening or colposcopy) versus delayed treatment (continued surveillance by screening or colposcopy, regardless of subsequent excision timing, or excision ≥6 months after initial CIN 2). MEASUREMENTS:3-year probability of potentially unnecessary excision (less severe than CIN 2 [<CIN 2]), and 3-year risks for CIN grade 3 or more severe (CIN 3+) or invasive cervical cancer after initial CIN 2. RESULTS:Immediate treatment was associated with a higher 3-year probability of <CIN 2 on excision compared with delayed treatment (36.2% vs. 7.8%). The IPW-standardized 3-year risks for cancer (0.39% vs. 0.43%) and CIN 3+ (8.85% vs. 10.31%) were similar under the 2 management strategies. LIMITATION:Lack of randomized assignment to interventions; cancer was rare. CONCLUSION:Immediate treatment did not reduce 3-year cancer risk compared with delayed treatment after CIN 2. Delaying treatment avoided some potentially unnecessary excisions but women with CIN 2 with immediate or delayed care were still at risk for cancer and required monitoring. PRIMARY FUNDING SOURCE:Intramural Research Program of the National Institutes of Health National Cancer Institute.

OBJECTIVES:The longer-term impact of introducing human papillomavirus (HPV) testing into routine cervical cancer screening on precancer and cancer rates by histologic type has not been well described. Calendar trends in diagnoses were examined using data from Kaiser Permanente Northern California, which introduced triennial HPV and cytology co-testing in 2003 for women aged ≥30 years. METHODS:We examined trends in cervical precancer (cervical intraepithelial neoplasia grade 3 [CIN3] and adenocarcinoma in situ [AIS]) and cancer (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]) diagnoses per 1000 screened during 2003-2018. We examined ratios of squamous vs. glandular diagnoses (SCC:ADC and CIN3:AIS). RESULTS:CIN3 and AIS diagnoses increased approximately 2% and 3% annually, respectively (ptrend < 0.001 for both). While SCC diagnoses decreased by 5% per annually (ptrend < 0.001), ADC diagnoses did not change. These patterns were generally observed within each age group (30-39, 40-49, and 50-64 years). ADC diagnoses per 1000 screened did not change even among those who underwent co-testing starting in 2003-2006. SCC:ADC decreased from approximately 2.5:1 in 2003-2006 to 1.3:1 in 2015-2018 while the CIN3:AIS remained relatively constant, ∼10:1. CONCLUSIONS:Since its introduction at KPNC, co-testing increased the detection of CIN3 over time, which likely caused a subsequent reduction of SCC. However, there has been no observed decrease in ADC. One possible explanation for lack of effectiveness against ADC is the underdiagnosis of AIS. Novel strategies to identify and treat women at high risk of ADC need to be developed and clinically validated.

BACKGROUND:Individuals with obesity have an increased risk of cervical cancer, in part related to challenges associated with cervical sampling and visualization that result in missed detection of cervical precancers. The influence of obesity on the effectiveness of excisional treatment of detected cervical precancers and posttreatment disease risk is unknown. OBJECTIVE:The aim of this study was to evaluate posttreatment risks of cervical precancer and cancer by body mass index (BMI). STUDY DESIGN:This retrospective cohort study included individuals aged 25 years and older undergoing excisional treatment for cervical precancer, either cervical intraepithelial neoplasia (CIN) grade 2 or 3 or adenocarcinoma in situ as of January 2017 with follow-up through February 2023. Patients were excluded if they were missing BMI, had cancer upon excision or had hysterectomy in lieu of excision, or were missing a valid referral screening visit. We categorized BMI as follows: underweight/normal (<25 kg/m2), overweight (25 to <30 kg/m2), and obesity (≥30kg/m2), as well as by class (I-III) of obesity. We calculated 2-year risks of CIN3 and cancer (combined as CIN3+) using Kaplan Meier methods and evaluated multivariable adjusted associations of BMI with CIN3+ using Cox Proportional Hazards regression analyses, accounting for age at treatment, race and ethnicity, and treatment type. RESULTS:Among 10,614 patients, a total of 680 (6.4%) developed post-treatment CIN3+; most (91%) within 2 years of treatment. Two-year CIN3+ and cancer risks were highest in those with obesity (8.65%, 95% CI, 7.6%-9.9% and 0.79%, 95% CI, 0.5%-1.2%, respectively) and lowest in those with normal weight (5.57%, 95% CI, 4.9%-6.3% and 0.29%, 95% CI, 0.2%-0.5%, respectively). Hazard ratios measuring associations of BMI with risk of posttreatment CIN3+ ranged from 1.19 (95% CI, 1.0-1.4) among those with overweight to 1.89 (95% CI, 1.4-2.6) among those with class III obesity (P-trend<.0001). A similar trend was observed for cancer, from 1.62 (95% CI, 0.8-3.3) for overweight and 3.50 (95% CI, 1.3-9.3) for class III obesity (P-trend=.016). CONCLUSION:Patients with obesity undergoing excisional treatment for cervical precancer have a higher risk of residual or recurrent disease, likely due to incomplete excision.

Table S1 shows type-specific associations of methylation with CIN3/AIS. Table S2 shows the correlation of methylation across CpG sites, by HPV type

Supplemental Table 1: Screening history of diagnosed cancer cases Supplemental Table 2: Outcome by age and baseline histology among women with conservatively managed CIN1/2, CIN2, CIN2/3 biopsy results

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. Endometrial and ovarian cancers could be amenable to similar testing. Methods: Between 2016 and 2020, discarded cervical cancer screening specimens from women ages 25 to 65 undergoing screening at Kaiser Permanente Northern California were collected. Specimens were aliquoted, stabilized, and stored frozen. Human papillomavirus (HPV), cytology, and histopathology results as well as demographic and cofactor information were obtained from electronic medical records (EMR). Follow-up collection of specimens was conducted for 2 years, and EMR-based data collection was planned for 5 years. Results: Collection of enrollment and follow-up specimens is complete, and EMR-based follow-up data collection is ongoing. At baseline, specimens were collected from 54,957 HPV-positive, 10,215 HPV-negative/Pap-positive, and 12,748 HPV-negative/Pap-negative women. Clinical history prior to baseline was available for 72.6% of individuals, of which 53.9% were undergoing routine screening, 8.6% recently had an abnormal screen, 30.3% had previous colposcopy, and 7.2% had previous treatment. As of February 2021, 55.7% had one or more colposcopies, yielding 5,563 cervical intraepithelial neoplasia grade 2 (CIN2), 2,756 cervical intraepithelial neoplasia grade 3 (CIN3), and 146 cancer histopathology diagnoses. Conclusions: This robust population-based cohort study represents all stages of cervical cancer screening, management, and posttreatment follow-up. Impact: The IRIS study is a unique and highly relevant resource allowing for natural history studies and rigorous evaluation of candidate HrHPV screening and triage markers, while permitting studies of biomarkers associated with other gynecologic cancers.

Objective The US screening and management guidelines for cervical cancer are based on the absolute risk of precancer estimated from large clinical cohorts and trials. Given the widespread transition toward screening with human papillomavirus (HPV) testing, it is important to assess which additional factors to include in clinical risk assessment to optimize management of HPV-infected women. Materials and Methods We analyzed data from HPV-infected women, ages 30–65 years, in the National Cancer Institute–Kaiser Permanente Northern California Persistence and Progression study. We estimated the influence of HPV risk group, cytology result, and selected cofactors on immediate risk of cervical intraepithelial neoplasia grade 3 or higher (CIN 3+) among 16,094 HPV-positive women. Cofactors considered included, age, race/ethnicity, income, smoking, and hormonal contraceptive use. Results Human papillomavirus risk group and cytology test result were strongly correlated with CIN 3+ risk. After considering cytology and HPV risk group, other cofactors (age, race/ethnicity, income, smoking, and hormonal contraceptive use) had minimal impact on CIN 3+ risk and did not change recommended management based on accepted risk thresholds. We had insufficient data to assess the impact of long-duration heavy smoking, parity, history of sexually transmitted infection, or immunosuppression. Conclusions In our study at the Kaiser Permanente Northern California, the risk of CIN 3+ was determined mainly by HPV risk group and cytology results, with other cofactors having limited impact in adjusted analyses. This supports the use of HPV and cytology results in risk-based management guidelines.

In this study of 320 men who have sex with men and are living with human immunodeficiency virus, we demonstrate that automated evaluation of p16/Ki-67 dual-stain cytology has high sensitivity for anal precancer and reduces unnecessary referral for high-resolution anoscopy, compared with manual evaluation. Background Human papillomavirus-related biomarkers such as p16/Ki-67 "dual-stain" (DS) cytology have shown promising clinical performance for anal cancer screening. Here, we assessed the performance of automated evaluation of DS cytology (automated DS) to detect anal precancer in men who have sex with men (MSM) and are living with human immunodeficiency virus (HIV). Methods We conducted a cross-sectional analysis of 320 MSM with HIV undergoing anal cancer screening and high-resolution anoscopy (HRA) in 2009-2010. We evaluated the performance of automated DS based on a deep-learning classifier compared to manual evaluation of DS cytology (manual DS) to detect anal intraepithelial neoplasia grade 2 or 3 (AIN2+) and grade 3 (AIN3). We evaluated different DS-positive cell thresholds quantified by the automated approach and modeled performance compared with other screening strategies in a hypothetical population of MSM with HIV. Results Compared with manual DS, automated DS had significantly higher specificity (50.9% vs 42.2%; P < .001) and similar sensitivity (93.2% vs 92.1%) for detection of AIN2+. Human papillomavirus testing with automated DS triage was significantly more specific than automated DS alone (56.5% vs 50.9%; P < .001), with the same sensitivity (93.2%). In a modeled analysis assuming a 20% AIN2+ prevalence, automated DS detected more precancers than manual DS and anal cytology (186, 184, and 162, respectively) and had the lowest HRA referral rate per AIN2+ case detected (3.1, 3.5, and 3.3, respectively). Conclusions Compared with manual DS, automated DS detects the same number of precancers, with a lower HRA referral rate.

As the US moves increasingly towards using human papillomavirus (HPV) testing with or without concurrent cytology for cervical cancer screening, it is unknown what the corresponding risks are following a screening result for women living with HIV (WLWH), which will dictate the optimal clinical follow-up. Therefore, using medical records data from Kaiser Permanente Northern California, which introduced triennial HPV and cytology co-testing in women aged 30-64 years in 2003, we compared risks of cervical intraepithelial neoplasia grade 2 (CIN2) or more severe diagnoses (CIN2+) in women not known to have HIV (HIV[-] women) (n = 67,488) frequency matched 111:1 on age and year of the first co-test to the 608 WLWH (n = 608). WLWH were more likely to test HPV positive (20.2% vs. 6.5%, p < 0.001) and have non-normal cytology (14.1% vs. 4.1%, p < 0.001) than HIV[-] women. Five-year CIN2+ risks for all WLWH and HIV[-] women were 3.5% (95%CI = 2.0-5.0%) and 1.6% (95%CI = 1.5-1.8%) (p = 0.01), respectively. Five-year CIN2+ risks for WLWH with positive HPV and non-normal cytology, positive HPV and normal cytology, negative HPV and non-normal cytology, and negative HPV and normal cytology were 24.9% (95%CI = 13.4-36.4%), 3.0% (95%CI = 0.0-7.4%), 3.6 (95%CI = 0.0-9.8%) and 0.3% (95%CI = 0.0-0.8%), respectively. Corresponding 5-year CIN2+ risks for HIV[-] women were 26.6% (95%CI = 24.6-28.7%), 8.5% (95%CI = 7.2-9.9%), 1.9% (95%CI = 1.0-2.8%), and 0.5% (95%CI = 0.4-0.6%), respectively. Thus, in this healthcare setting, the main cause in overall CIN2+ risk differences between WLWH and HIV[-] women was the former was more likely to screen positive and once the screening result is known, it may be reasonable to manage both populations similarly.

In Brief The majority of cervical cancers after Pap test–positive, human papillomavirus test–negative co-tests are symptomatic or clinically apparent.

Background With the advent of primary human papillomavirus testing followed by cytology for cervical cancer screening, visual interpretation of cytology slides remains the last subjective analysis step and suffers from low sensitivity and reproducibility. Methods We developed a cloud-based whole-slide imaging platform with a deep-learning classifier for p16/Ki-67 dual-stained (DS) slides trained on biopsy-based gold standards. We compared it with conventional Pap and manual DS in 3 epidemiological studies of cervical and anal precancers from Kaiser Permanente Northern California and the University of Oklahoma comprising 4253 patients. All statistical tests were 2-sided. Results In independent validation at Kaiser Permanente Northern California, artificial intelligence (AI)-based DS had lower positivity than cytology (P < .001) and manual DS (P < .001) with equal sensitivity and substantially higher specificity compared with both Pap (P < .001) and manual DS (P < .001), respectively. Compared with Pap, AI-based DS reduced referral to colposcopy by one-third (41.9% vs 60.1%, P < .001). At a higher cutoff, AI-based DS had similar performance to high-grade squamous intraepithelial lesions cytology, indicating a risk high enough to allow for immediate treatment. The classifier was robust, showing comparable performance in 2 cytology systems and in anal cytology. Conclusions Automated DS evaluation removes the remaining subjective component from cervical cancer screening and delivers consistent quality for providers and patients. Moving from Pap to automated DS substantially reduces the number of colposcopies and also achieves excellent performance in a simulated fully vaccinated population. Through cloud-based implementation, this approach is globally accessible. Our results demonstrate that AI not only provides automation and objectivity but also delivers a substantial benefit for women by reduction of unnecessary colposcopies.

Introduction: : Biomarkers of Human Papillomavirus (HPV) cervical carcinogenesis are critical to address questions of how to triage and manage women who screen positive for high-risk HPV (HrHPV) and identify those at highest cancer risk. Methods: : We describe the development of a large biorepository of cervical specimens for the Improving Risk Informed HPV Screening Study (IRIS) using residual specimens collected in the regional laboratory from women aged 25 and older who had cervical cancer screening or follow-up testing with high-risk human papillomavirus (HrHPV) testing and liquid-based cytology (co-testing) at Kaiser Permanente Northern California (KPNC) from January 2016 to August 2018. Specimen selection, processing for long-term storage, follow-up tracking, consent and demographic and clinical characteristics of the women in the IRIS cohort are described. Results: : Selecting from 897,680 women who had at least one co-test during the study period, we collected 199,403 baseline and 216,390 follow-up HrHPV and cytology specimens from a stratified random sample of 81,348 women, of which 3,428 (4.2%) opted out of the study and were excluded. The majority (79.9%) of the baseline specimens were from HrHPV-positive women. The mean age was 36 years, and the cohort is racially/ ethnically diverse with 56% of women being Hispanic or non-white. Over two-thirds of the cohort were members of KPNC for two or more years prior to inclusion. Of the 77,920 women included in the cohort, 57,414 (73.7%) had at least one follow-up co-test. Conclusion: : Use of specimens from the biorepository will elucidate molecular mechanisms underlying HPV carcinogenesis and inform more effective screening and follow-up strategies.

Background. To investigate whether routine cervical screening using human papillomavirus (HPV) and cytology co-testing effectively identifies women with endometrial (EC) or ovarian (OvC) cancer. Methods. In 2003, Kaiser Permanente Northern California implemented triennial co-testing in women aged >= 30 years. Index screening results (n = 2,385,729) were linked to subsequent EC (n = 3434) and OvC (n = 1113) diagnoses from January 1,2003 to December 31, 2017. EC were categorized as type 1 or 2, and, selectively, EC and OvC diagnoses were stratified on whether symptoms were present at the time of the co-test. Fractions and absolute risks of EC or OvC of each co-testing result were calculated. Results. Most EC (82.18%) and OvC (88.68%) were preceded by a negative HPV and negative cytology co-test. More EC were preceded by atypical squamous cells of undetermined significance (ASC-US) or more severe (ASCUS+ ) cytology and negative HPV test (n = 290) (8.44% of EC) compared to a negative cytology and a positive HPV test (n = 31) (0.89% of EC) (p < 0.001). The absolute risk of any EC diagnosis following ASC-US+ and negative HPV test was 0.48%. Atypical glandular cells (AGC) cytology and a negative HPV result preceded 6.92% of any EC diagnosis, with an absolute risk of 4.02%, but preceded only 1.13% of type 2 EC cases, with an absolute risk of 0.24%, in asymptomatic women. AGC cytology and a negative HPV result preceded 1.44% of OvC, with an absolute risk of 028%. Conclusions. Abnormal cervical screening tests, even AGC cytology, rarely precedes and poorly predict women with EC or OvC. (C) 2021 Published by Elsevier Inc.

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. METHODS:Risk estimates were drawn from a subset of women in the Kaiser Permanente Northern California screening program, whose residual cervical specimens were HPV typed as part of the HPV Persistence and Progression study. We calculated risk of CIN 3+ to assess how identification of HPV 16, HPV 18, or 12 other "high-risk" HPV types would influence recommended clinical management of new abnormal screening results, taking into account current cytologic results and recent screening history. Immediate and/or 5-year risks of CIN 3+ were matched to clinical actions identified in the guidelines. RESULTS:Identification of HPV 16 at the first visit including HPV testing elevated immediate risk of diagnosing CIN 3+ sufficiently to mandate colposcopic referral even when cytology was Negative for Intraepithelial Lesions or Malignancy and to support a preference for treatment of cytologic high-grade squamous intraepithelial lesion. HPV 18 less clearly elevated CIN 3+ risk. CONCLUSIONS:Identification of HPV 16 clearly mandated consideration in clinical management of new abnormal screening results. HPV 18 positivity must be considered as a special situation because of established disproportionate risk of invasive cancer. More detailed genotyping and use beyond initial management will be considered in guideline updates.

HPV35 has been found in only similar to 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. and internationally. Combining five U.S. studies, we measured HPV35 positivity and, in Northern California, observed HPV35 type-specific population prevalence and estimated 5-year risk of developing precancer when HPV35-positive. HPV35 genetic variation was examined for differences in carcinogenicity in 1053 HPV35+ cervical specimens from a U.S. cohort and an international collection. African-American women had more HPV35 (12.1% vs 5.1%, P < .001) and more HPV35-associated precancers (7.4% vs 2.1%, P < .001) compared to other ethnicities. Precancer risks after HPV35 infection did not vary by ethnicity (global P = .52). The HPV35 A2 sublineage showed an increased association with precancer/cancer in African-Americans (OR = 5.6 vs A1, 95% CI = 1.3-24.8) and A2 was more prevalent among ICC in Africa than other world regions (41.9% vs 10.4%, P < .01). Our analyses support a strong link between HPV35 and cervical carcinogenesis in women of African ancestry. Current HPV vaccines cover the majority of cervical precancer/cancer across all ethnic groups; additional analyses are required to determine whether the addition of HPV35 to the already highly effective nine-valent HPV vaccine would provide better protection for women in Africa or of African ancestry.

Many countries are transitioning to HPV testing for cervical cancer screening, despite a lack of long‐term experience. To anticipate multi‐round screening performance, we analyzed 15‐year HPV testing results at Kaiser Permanente Northern California (KPNC). We evaluated HPV test result patterns among women aged 30–64 undergoing triennial HPV/cytology cotesting at KPNC during 2003–2018. We calculated incidence rates and proportion of CIN3+ diagnoses associated with the most frequent HPV testing patterns overall and stratified by age. From 2003 to 2018, a total of 1,361,581 women had a valid HPV test result, and 7,087 were diagnosed with CIN3+. Incidence rates of CIN3+ after HPV positivity were lowest when HPV detection was new and highest in women with prevalent infections (770 vs . 13,910/100,000 person‐years). Repeat test negativity reduced subsequent incidence rates of CIN3+ to extremely low levels (18/100,000 person‐years following four consecutive negative results). For mixed patterns of positivity/negativity, the recency and frequency of positive tests were associated with increased rates of CIN3+ diagnosis. Most CIN3+ cases (76%) were diagnosed in women who were positive at baseline (the first known positive HPV result); 16% were attributed to apparent newly detected infections and 3% to possible reappearing infections. These results corroborate previous findings that current HPV positivity, particularly when prevalent rather than new, is associated with the highest rates of CIN3+. In a screening program implementing HPV testing, most CIN3+ is detected at the first HPV positive test.

Background: HPV testing is replacing cytology for cervical cancer screening because of greater sensitivity and superior reassurance following negative tests for the dozen HPV genotypes that cause cervical cancer. Management of women testing positive is unresolved. The need for identification of individual HPV genotypes for clinical use is debated. Also, it is unclear how long to observe persistent infections when precancer is not initially found. Methods: In the longitudinal NCI-Kaiser Permanente Northern California Persistence and Progression (PaP) Study, we observed the clinical outcomes (clearance, progression to CIN3+, or persistence without progression) of 11,573 HPV-positive women aged 30–65 yielding 14,158 type-specific infections. Findings: Risks of CIN3+ progression differed substantially by type, with HPV16 conveying uniquely elevated risk (26% of infections with seven-year CIN3+ risk of 22%). The other carcinogenic HPV types fell into 3 distinct seven-year CIN3+ risk groups: HPV18, 45 (13% of infections, risks >5%, with known elevated cancer risk); HPV31, 33, 35, 52, 58 (39%, risks >5%); and HPV39, 51, 56, 59, 68 (23%, risks <5%). In the absence of progression, HPV clearance rates were similar by type, with 80% of infections no longer detected within three years; persistence to seven years without progression was uncommon. The predictive value of abnormal cytology was most evident for prevalent CIN3+, but less evident in follow-up. A woman's age did not modify risk; rather it was the duration of persistence that was important. Interpretation: HPV type and persistence are the major predictors of progression to CIN3+; at a minimum, distinguishing HPV16 is clinically important. Dividing the other HPV types into three risk-groups is worth considering.

IMPORTANCE As cervical cancer screening transitions from Papanicolaou cytologic screening to primary human papillomavirus (HPV) testing worldwide, effective triage tests are needed to decide who among the HPV-positive women should receive further diagnostic evaluation to avoid unnecessary colposcopies and biopsies. OBJECTIVE To evaluate the performance of the p16/Ki-67 dual stain (DS) and HPV16/18 genotyping for the triage of HPV-positive women. DESIGN, SETTING, AND PARTICIPANTS A prospective observational study was conducted within the cervical cancer screening program at Kaiser Permanente Northern California of 3225 HPV-positive women undergoing HPV and Papanicolaou cytologic testing with a valid DS result from September 16 to October 31, 2015, with follow-up through December 31, 2018. EXPOSURES Human papillomavirus screening with partial genotyping and cytologic triage compared with DS triage. MAIN OUTCOMES AND MEASURES Cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) and grade 2 or more severe (CIN2+), diagnosed within 3 years after sample collection. RESULTS A total of 3225 women (mean [SD] age, 37.9 [11.3] years) participated in the study. For triage of HPV-positive women with partial genotyping, DS showed better risk stratification for CIN3+ than did Papanicolaou cytologic testing, with women with positive DS results having a higher risk than women with positive Papanicolaou test results for CIN3+ (218 of 1818 [12.0%; 95% CI, 10.5%-13.5%] vs 219 of 2128 [10.3%; 95% CI, 9.0%-11.6%]; P=.005). Similarly, DS showed better risk stratification for CIN3+ compared with Papanicolaou cytologic testing in HPV-positive women, irrespective of genotyping. The greatest reassurance against CIN3+ was observed in HPV16/18-negative women with negative DS results, with a risk low enough to extend retesting intervals. Dual stain triage strategies required substantially fewer colposcopies per detection of CIN3+ compared with Papanicolaou cytologic testing, with a 32.1% (859 of 2677) reduction of colposcopies compared with the currently recommended triage strategy of HPV screening with Papanicolaou cytologic testing. Results for CIN2+ were very similar. CONCLUSIONS AND RELEVANCE Triage of HPV-positive women with DS was superior to Papanicolaou cytologic testing in this study, demonstrating equal immediate detection of precancerous lesions and substantially reduced referral to colposcopy. These findings suggest that DS can safely replace Papanicolaou cytologic testing as a triage strategy for primary HPV screening, and that retesting intervals in HPV16/18-negative women with negative DS results can be safely extended to 3 years.

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). Women with a history of excisional treatment or CIN2+ were excluded. No woman with one or more negative cotests was diagnosed with cancer during follow‐up. Five‐year risks of CIN3 after one, two, and three consecutive negative cotests were 0.034% (95% CI: 0.023%–0.046%), 0.041% (95% CI: 0.007%–0.076%) and 0.016% (95% CI: 0.000%–0.052%), respectively (ptrend < 0.001). These risks did not appreciably differ by a positive cotest result prior to the one, two or three negative cotest(s). Since CIN3 risks after one or more negative cotests were significantly below a proposed 0.12% CIN3+ risk threshold for a 5‐year screening interval, a longer screening interval in these women is justified. However, the choice of how many negative cotests provide sufficient safety against invasive cancer over a woman's remaining life represents a value judgment based on the harms versus benefits of continued screening. Ideally, this guideline should be informed by longer‐term follow‐up given that exiting is a long‐term decision.