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. Objective: To measure cervical cancer risk in routine practice after successive negative screening co-tests at 3-year intervals. Design: Observational cohort study. Setting: Integrated health care system (Kaiser Permanente Northern California, Oakland, California). Patients: 990 013 women who had 1 or more co-tests from 2003 to 2014. Measurements: 3- and 5-year cumulative detection of (risk for) cervical intraepithelial neoplasia grade 3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in women with different numbers of negative co-tests, overall and within subgroups defined by previous co-test results or baseline age. Results: Five-year ≥CIN3 risks decreased after each successive negative co-test screening round (0.098%, 0.052%, and 0.035%). Five-year ≥CIN3 risks for an HPV-negative co-test, regardless of the cytology result, nearly matched the performance (reassurance) of a negative co-test for each successive round of screening (0.114%, 0.061%, and 0.041%). By comparison, ≥CIN3 risks for the cytology-negative co-test, regardless of the HPV result, also decreased with each successive round, but 3-year risks were as high as 5-year risks after an HPV-negative co-test (0.199%, 0.065%, and 0.043%). No interval cervical cancer cases were diagnosed after the second negative co-test. Independently, ≥CIN3 risks decreased with age. Length of previous screening interval did not influence future ≥CIN3 risks. Limitation: Interval-censored observational data. Conclusion: After 1 or more negative cervical co-tests (or HPV tests), longer screening intervals (every 5 years or more) might be feasible and safe. Primary Funding Source: National Cancer Institute Intramural Research Program.

Validation of a Human Papillomavirus (HPV) DNA Cervical Screening Test That Provides Expanded HPV Typing.

As cervical cancer screening shifts from cytology to human papillomavirus (HPV) testing, a major question is the clinical value of identifying individual HPV types. We aimed to validate Onclarity (Becton Dickinson Diagnostics, Sparks, MD), a nine-channel HPV test recently approved by the FDA, by assessing (i) the association of Onclarity types/channels with precancer/cancer; (ii) HPV type/channel agreement between the results of Onclarity and cobas (Roche Molecular Systems, Pleasanton, CA), another FDA-approved test; and (iii) Onclarity typing for all types/channels compared to typing results from a research assay (linear array [LA]; Roche). We compared Onclarity to histopathology, cobas, and LA. We tested a stratified random sample (n = 9,701) of discarded routine clinical specimens that had tested positive by Hybrid Capture 2 (HC2; Qiagen, Germantown, MD). A subset had already been tested by cobas and LA (n = 1,965). Cervical histopathology was ascertained from electronic health records. Hierarchical Onclarity channels showed a significant linear association with histological severity. Onclarity and cobas had excellent agreement on partial typing of HPV16, HPV18, and the other 12 types as a pool (sample-weighted kappa value of 0.83); cobas was slightly more sensitive for HPV18 and slightly less sensitive for the pooled high-risk types. Typing by Onclarity showed excellent agreement with types and groups of types identified by LA (kappa values from 0.80 for HPV39/68/35 to 0.97 for HPV16). Onclarity typing results corresponded well to histopathology and to an already validated HPV DNA test and could provide additional clinical typing if such discrimination is determined to be clinically desirable.

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 (<2.5years), adherent (2.5<3.5years), or late (3.5<6.0years). We also examined repeated early screening in a subgroup of 50,691 women. Predictors examined included: cohort year (defined by baseline cotest, 2003-2009), race/ethnicity, and baseline age. Compared to the 2003 cohort, women in the 2009 cohort were significantly less likely to screen early (aOR=0.22, 95% CI=0.21, 0.23) or late (aOR=0.47, 95% CI=0.45, 0.49). African American (AA) and Hispanic women were less adherent overall than Non-Hispanic White women, with increased early [(AA: aOR=1.21, 95%CI=1.17, 1.25) (Hispanic: aOR=1.08, 95%CI=1.06, 1.11)] and late screening [(AA: aOR=1.23, 95%CI=1.19, 1.27) (Hispanic: aOR=1.06, 95%CI=1.03, 1.08)]. Asian women were slightly more likely to screen early (aOR=1.03, 95%CI=1.01, 1.05), and less likely to screen late (aOR=0.92, 95% CI=0.90, 0.94). Women aged 60-64years were most likely to screen early for two consecutive intervals (aOR=2.09, 95%CI=1.91, 2.29). Our study found that widespread and rapid adoption of extended interval cervical cancer screening is possible, at least in this managed care setting. Further research examining multilevel drivers promoting or restricting extended interval screening across diverse healthcare settings is needed.

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. Here we demonstrate how the choice of statistical method can impact risk estimates. We use observed data on 41,067 women in the cervical cancer screening program at Kaiser Permanente Northern California, 2003-2013, as well as simulations to evaluate the ability of different methods (Kaplan-Meier, Turnbull, Weibull and logistic-Weibull) to accurately estimate risk within a screening program. Cumulative risk estimates from the statistical methods varied considerably, with the largest differences occurring for prevalent disease risk when baseline disease ascertainment was random but incomplete. Kaplan-Meier underestimated risk at earlier times and overestimated risk at later times in the presence of interval censoring or undiagnosed prevalent disease. Turnbull performed well, though was inefficient and not smooth. The logistic-Weibull model performed well, except when event times didn't follow a Weibull distribution. We have demonstrated that methods for right-censored data, such as Kaplan-Meier, result in biased estimates of disease risks when applied to interval-censored data, such as screening programs using EHR data. The logistic-Weibull model is attractive, but the model fit must be checked against Turnbull non-parametric risk estimates.

Low Risk of Cervical Cancer/Precancer Among Most Women Under Surveillance Postcolposcopy.

OBJECTIVE: To inform impending postcolposcopy guidelines, this analysis examined the subsequent risk of CIN 3+ among women with a grade lower than CIN 2 (< CIN 2) colposcopy results, taking into account the referring results that brought them to colposcopy and cotest results postcolposcopy. METHODS: We analyzed 107,005 women from 25 to 65 years old, recommended for colposcopy at Kaiser Permanente Northern California. We estimated absolute risks of CIN 3+ among women: (1) recommended for colposcopy (precolposcopy), (2) following colposcopy and with histology results < CIN 2 (postcolposcopy), and (3) with cotest results 12 months after a < CIN 2 colposcopy (return cotest). RESULTS: After colposcopy showing < CIN 2 (n = 69,790; 87% of the women at colposcopy), the 1-year risk of CIN 3+ was 1.2%, compared with 6.3% at the time of colposcopy recommendation. Negative cotest results 1 year after colposcopy identified a large group (37.1%) of women whose risk of CIN 3+ (i.e., <0.2% at 3 years after postcolposcopy cotest) was comparable with women with normal cytology in the screening population. These risks are consistent with current guidelines recommending repeat cotesting 12 months after colposcopy < CIN 2 and a 3-year return for women with a negative postcolposcopy cotest. CONCLUSIONS: Most women are at low risk of subsequent CIN 3+ after a colposcopy showing < CIN 2, especially those who are human papillomavirus-negative postcolposcopy, consistent with current management guidelines for repeat testing intervals. Before the finalizing the upcoming guidelines, we will consider additional rounds of postcolposcopy cotesting.

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. National Cancer Institute Persistence and Progression Study, we assessed the agreement and clinical performance of a simple, inexpensive real-time PCR assay for the detection of 13 carcinogenic HPV types (the H13 assay; Hybribio, Hong Kong) that is marketed in limited-resource settings compared to previous testing by the Hybrid Capture 2 assay (HC2; Qiagen, Germantown, MD) and the Onclarity assay (BD Diagnostics, Sparks, MD). The test set was chosen to include many HPV-positive specimens. The reference standard was a combination of HC2 and Onclarity results for HPV detection and histologic diagnosis of controls (less than cervical intraepithelial neoplasia grade 2 [

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. We calculated surrogate measures of programmatic effectiveness (precancers/(precancers and cancers)) and diagnostic yield (precancers and cancers per 1000 cotests), overall and by age at cotest (30-39, 40-49, and ≥50years). RESULTS: Cancer was rare and found mainly in a localized (treatable) stage. Of 623 cervical cancers with at least one preceding or concurrent cotest, 360 (57.8%) were judged to be prevalent (diagnosed at a localized stage within one year or regional/distant stage within two years of the first cotest). Non-compliance with recommended screening and management preceded 9.0% of all cancers. False-negative cotests/sampling errors (HPV and cytology negative), false-negative histologic diagnoses, and treatment failures preceded 11.2%, 9.0%, and 4.3%, respectively, of all cancers. There was significant heterogeneity in the causes of cancer by histologic category (p<0.001 for all; p=0.002 excluding prevalent cases). Programmatic effectiveness (95.3%) and diagnostic yield were greater for squamous cell versus adenocarcinoma histology (p<0.0001) and both decreased with older ages (ptrend<0.0001). CONCLUSIONS: A state-of-the-art intensive screening program results in very few cervical cancers, most of which are detected early by screening. Screening may become less efficient at older ages.

Mixture models for undiagnosed prevalent disease and interval-censored incident disease: applications to a cohort assembled from electronic health records.

For cost-effectiveness and efficiency, many large-scale general-purpose cohort studies are being assembled within large health-care providers who use electronic health records. Two key features of such data are that incident disease is interval-censored between irregular visits and there can be pre-existing (prevalent) disease. Because prevalent disease is not always immediately diagnosed, some disease diagnosed at later visits are actually undiagnosed prevalent disease. We consider prevalent disease as a point mass at time zero for clinical applications where there is no interest in time of prevalent disease onset. We demonstrate that the naive Kaplan-Meier cumulative risk estimator underestimates risks at early time points and overestimates later risks. We propose a general family of mixture models for undiagnosed prevalent disease and interval-censored incident disease that we call prevalence-incidence models. Parameters for parametric prevalence-incidence models, such as the logistic regression and Weibull survival (logistic-Weibull) model, are estimated by direct likelihood maximization or by EM algorithm. Non-parametric methods are proposed to calculate cumulative risks for cases without covariates. We compare naive Kaplan-Meier, logistic-Weibull, and non-parametric estimates of cumulative risk in the cervical cancer screening program at Kaiser Permanente Northern California. Kaplan-Meier provided poor estimates while the logistic-Weibull model was a close fit to the non-parametric. Our findings support our use of logistic-Weibull models to develop the risk estimates that underlie current US risk-based cervical cancer screening guidelines. Published 2017. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

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. RESULTS: Ninety percent of screened women had HPV-negative NILM and an extremely low risk of subsequent cancer. Five-year risks of CIN 3+ were lower after HPV negativity (0.12%) than after NILM (0.25%). Among HPV-negative women, 5-year risks for CIN 3+ were 0.10% for NILM, 0.44% for ASC-US, 1.8% for LSIL, 3.0% for ASC-H, 1.2% for AGC, and 29% for HSIL+ cytology (which was very rare). Among HPV-positive women, 5-year risks were 4.0% for NILM, 6.8% for ASC-US, 6.1% for LSIL, 28% for ASC-H, 30% for AGC, and 50% for HSIL+ cytology. CONCLUSIONS: As a foundation for the next guidelines revision, we confirmed with additional precision the risk estimates previously reported for combinations of HPV and cytology. Future analyses will estimate risks for women being followed in colposcopy clinic and posttreatment and will consider the role of risk modifiers such as age, HPV vaccine status, HPV type, and screening and treatment history.

A cohort study of cervical screening using partial HPV typing and cytology triage.

HPV testing is more sensitive than cytology for cervical screening. However, to incorporate HPV tests into screening, risk-stratification ("triage") of HPV-positive women is needed to avoid excessive colposcopy and overtreatment. We prospectively evaluated combinations of partial HPV typing (Onclarity, BD) and cytology triage, and explored whether management could be simplified, based on grouping combinations yielding similar 3-year or 18-month CIN3+ risks. We typed ∼9,000 archived specimens, taken at enrollment (2007-2011) into the NCI-Kaiser Permanente Northern California (KPNC) HPV Persistence and Progression (PaP) cohort. Stratified sampling, with reweighting in the statistical analysis, permitted risk estimation of HPV/cytology combinations for the 700,000+-woman KPNC screening population. Based on 3-year CIN3+ risks, Onclarity results could be combined into five groups (HPV16, else HPV18/45, else HPV31/33/58/52, else HPV51/35/39/68/56/66/68, else HPV negative); cytology results fell into three risk groups ("high-grade," ASC-US/LSIL, NILM). For the resultant 15 HPV group-cytology combinations, 3-year CIN3+ risks ranged 1,000-fold from 60.6% to 0.06%. To guide management, we compared the risks to established "benchmark" risk/management thresholds in this same population (e.g., LSIL predicted 3-year CIN3+ risk of 5.8% in the screening population, providing the benchmark for colposcopic referral). By benchmarking to 3-year risk thresholds (supplemented by 18-month estimates), the widely varying risk strata could be condensed into four action bands (very high risk of CIN3+ mandating consideration of cone biopsy if colposcopy did not find precancer; moderate risk justifying colposcopy; low risk managed by intensified follow-up to permit HPV "clearance"; and very low risk permitting routine screening.) Overall, the results support primary HPV testing, with management of HPV-positive women using partial HPV typing and cytology.

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. The effect on screening efficiency, defined as numbers of cotests/colposcopy visits needed to detect a precancer, also was considered. METHODS: Two cohorts were defined. The "open cohort" included all women screened at least once during the study period; > 1 million cotests were performed. In a fixed "long-term screening cohort," the authors considered the cumulative impact of repeated screening at 3-year intervals by restricting the cohort to women first cotested in 2003 through 2004 (ie, no women entering screening later were added to this group). RESULTS: Detection of cervical intraepithelial neoplasia 3/adenocarcinoma in situ (CIN3/AIS) increased in the open cohort (2004-2006: 82.0/100,000 women screened; 2007-2009: 140.6/100,000 women screened; and 2010-2012: 126.0/100,000 women screened); cancer diagnoses were unchanged. In the long-term screening cohort, the detection of CIN3/AIS increased and then decreased to the original level (2004-2006: 80.5/100,000 women screened; 2007-2009: 118.6/100,000 women screened; and 2010-2012: 84.9./100,000 women screened). The number of cancer diagnoses was found to decrease. When viewed in terms of screening efficiency, the number of colposcopies performed to detect a single case of CIN3/AIS increased in the cohort with repeat screening. CONCLUSIONS: Repeated cotesting at a 3-year interval eventually lowers population rates of precancer and cancer. However, a greater number of colposcopies are required to detect a single precancer. Cancer 2016;122:3682-6. © 2016 American Cancer Society.

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. Women (57,899, 6.0%) had an enrollment HPV infection. Among the women testing HPV negative at enrollment with a second screening visit, 16,724 (3.3%) had a newly detected HPV infection at their second visit. Both enrollment and newly detected HPV rates declined with age (p < 0.001). Women with enrollment versus newly detected HPV infection had higher 5-year CIN3+ risks: 8.5% versus 3.9%, (p < 0.0001). Risks did not increase with age but declined slightly from 30-34 years to 60-64 years: 9.4% versus 7.4% (p = 0.017) for enrollment HPV and 5.1% versus 3.5% (p = 0.014) for newly detected HPV. Among women age 30-64 in an established screening program, women with newly detected HPV infections were at lower risk than women with enrollment infections, suggesting reduced benefit vaccinating women at older ages. Although the rates of HPV infection declined dramatically with age, the subsequent CIN3+ risks associated with HPV infection declined only slightly. The CIN3+ risks among older women are sufficiently elevated to warrant continued screening through age 65.

A study of HPV typing for the management of HPV-positive ASC-US cervical cytologic results.

BACKGROUND: In US cervical screening, immediate colposcopy is recommended for women with HPV-positive ASC-US (equivocal) cytology. We evaluated whether partial typing by Onclarity™ (BD) might identify HPV-positive women with low enough CIN3+ risk to permit 1-year follow-up instead. METHODS: The NCI-Kaiser Permanente Northern California Persistence and Progression cohort includes a subset of 13,890 women aged 21+ with HC2 (Qiagen)-positive ASC-US at enrollment; current median follow-up is 3.0years. Using stratified random sampling, we typed 2079 archived enrollment specimens including 329 women subsequently diagnosed with CIN3+, 563 with CIN2, and 1187 with

Analytic and clinical performance of cobas HPV testing in anal specimens from HIV-positive men who have sex with men.

Anal human papillomavirus (HPV) infections are common, and the incidence of anal cancer is high in HIV-infected men who have sex with men (MSM). To evaluate the performance of HPV assays in anal samples, we compared the cobas HPV test (cobas) to the Roche Linear Array HPV genotyping assay (LA) and cytology in HIV-infected MSM. Cytology and cobas and LA HPV testing were conducted for 342 subjects. We calculated agreement between the HPV assays and the clinical performance of HPV testing and HPV genotyping alone and in combination with anal cytology. We observed high agreement between cobas and LA, with cobas more likely than LA to show positive results for HPV16, HPV18, and other carcinogenic types. Specimens testing positive in cobas but not in LA were more likely to be positive for other markers of HPV-related disease compared to those testing negative in both assays, suggesting that at least some of these were true positives for HPV. cobas and LA showed high sensitivities but low specificities for the detection of anal intraepithelial neoplasia grade 2/3 (AIN2/3) in this population (100% sensitivity and 26% specificity for cobas versus 98.4% sensitivity and 28.9% specificity for LA). A combination of anal cytology and HPV genotyping provided the highest accuracy for detecting anal precancer. A higher HPV load was associated with a higher risk of AIN2/3 with HPV16 (P(trend) < 0.001), HPV18 (P(trend) = 0.07), and other carcinogenic types (P(trend) < 0.001). We demonstrate that cobas can be used for HPV detection in anal cytology specimens. Additional tests are necessary to identify men at the highest risk of anal cancer among those infected with high-risk HPV.

Cervical cancer rates after the transition from annual Pap to 3-year HPV and Pap.

OBJECTIVE: Kaiser Permanente Northern California (KPNC) introduced 3-year Pap and human papillomavirus DNA cotesting for cervical cancer screening in women 30 years or older in 2003 to 2004. Patient and provider willingness to extend screening intervals and the impact on annual cervical cancer incidence after interval extension are evaluated. MATERIALS AND METHODS: Age-adjusted cervical cancer rates and screening intervals were calculated from KPNC Regional Laboratory databases and Northern California Cancer Registry from 2000 to 2009. RESULTS: The median screening interval between negative cotests was 36 months compared to the 16 months after a negative Pap test alone before the implementation of cotesting. The age-adjusted invasive cancer rate was 6.5 per 100,000 women in 2000 and 6.3 in 2009; there was no difference in the rates of cervical cancer in women 30 years or older from 2000 to 2009 (p(trend) = .7). CONCLUSIONS: Patients and providers were compliant with the extension of screening intervals with cotesting. Cervical cancer rates remained constant during the 10-year study period despite extending screening intervals after a negative cotest.

Human papillomavirus genotype attribution and estimation of preventable fraction of anal intraepithelial neoplasia cases among HIV-infected men who have sex with men.

BACKGROUND: The prevention of human papillomavirus (HPV)-induced anal cancer in high-risk populations such as human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) remains an urgent priority, given rising incidence rates despite widespread antiretroviral therapy use. METHODS: HPV genotypes and anal disease prevalence, by cytology and histopathologic findings, were evaluated among 363 HIV-infected MSM. We modeled fractions of high-grade anal intraepithelial neoplasia (HGAIN) attributable to individual carcinogenic HPV genotypes and estimated the range of the proportion of HGAIN cases potentially preventable by prophylactic HPV vaccines. RESULTS: HPV16 was the most common genotype overall (26.4% of cases) and among HGAIN cases (55%). Prevalence of multiple (≥ 2) carcinogenic HPV genotypes increased from 30.9% in cases of AIN grade <1 to 76.3% in cases of AIN grade 3 (P(trend) < .001). The fractions of HGAIN cases attributable to carcinogenic HPV16/18 targeted by currently licensed bivalent and quadrivalent HPV vaccines ranged from 12% to 61.5%, and the fractions attributable to carcinogenic HPV16/18/31/33/45/52/58 targeted by an investigational nonavalent HPV vaccine ranged from 39% to 89.4%. CONCLUSIONS: Our analytical framework allows estimation of HGAIN cases attributable to individual HPV genotypes in the context of multiple concurrent HPV infections, which are very common among HIV-infected MSM. Our results suggest that licensed and investigational HPV prophylactic vaccines have the potential to prevent a substantial proportion of HGAIN cases in this population.

Risk factors for anal HPV infection and anal precancer in HIV-infected men who have sex with men.

BACKGROUND: Carcinogenic human papillomaviruses (HPVs) cause a large proportion of anal cancers. Human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) are at increased risk of HPV infection and anal cancer compared with HIV-negative men. We evaluated risk factors for HPV infection and anal precancer in a population of HIV-infected MSM. METHODS: Our study included 305 MSM at an HIV/AIDS clinic in the Kaiser Permanente Northern California Health Maintenance Organization. Logistic regression was used to estimate associations of risk factors comparing men without anal HPV infection; men with anal HPV infection, but no precancer; and men with anal precancer. RESULTS: Low CD4 count (<350 cells/mm(3)) and previous chlamydia infection were associated with an increased risk of carcinogenic HPV infection (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.28-10.40 and OR, 4.24; 95% CI, 1.16-15.51, respectively). History of smoking (OR, 2.71 95% CI, 1.43-5.14), duration, recency, and dose of smoking increased the risk of anal precancer among carcinogenic HPV-positive men but had no association with HPV infection. CONCLUSIONS: We found distinct risk factors for anal HPV infection and anal precancer. Risk factors for HPV infection and anal precancer are similar to established risk factors for cervical cancer progression.

Prevalence of HPV types in cervical specimens from an integrated healthcare delivery system: baseline assessment to measure HPV vaccine impact.

PURPOSE: Two human papillomavirus (HPV) vaccines are available to prevent cervical cancer. One early measure of HPV vaccine impact would be a reduction in vaccine-related HPV types (HPV 6, 11, 16, or 18, or HPV 16, 18) in cervical samples from young women. We aimed to assess feasibility of specimen collection and baseline HPV prevalence in an integrated healthcare delivery system. METHODS: Residual cervical specimens collected during routine cervical cancer screening (2006-2008) were retained consecutively from eligible females aged 11-29 years, stratified by age group. Specimens were evaluated for 37 HPV genotypes using the Roche Linear Array assay. RESULTS: Of 10,124 specimens submitted, 10,103 (99 %) were adequate for HPV testing. Prevalence of HPV 6, 11, 16, or 18 genotype was 11.4 % overall and was the highest in the youngest age group (18.1 % in the 11-19-year-olds, 12.5 % in the 20-24-year-olds, and 7.0 % in the 25-29-year-olds). CONCLUSIONS: HPV types 6, 11, 16, or 18 prevalence could be measured over time to assess early HPV vaccine impact using residual specimens from an integrated healthcare delivery system, particularly if sampling focused on young women.

A general binomial regression model to estimate standardized risk differences from binary response data.

Estimates of absolute risks and risk differences are necessary for evaluating the clinical and population impact of biomedical research findings. We have developed a linear-expit regression model (LEXPIT) to incorporate linear and nonlinear risk effects to estimate absolute risk from studies of a binary outcome. The LEXPIT is a generalization of both the binomial linear and logistic regression models. The coefficients of the LEXPIT linear terms estimate adjusted risk differences, whereas the exponentiated nonlinear terms estimate residual odds ratios. The LEXPIT could be particularly useful for epidemiological studies of risk association, where adjustment for multiple confounding variables is common. We present a constrained maximum likelihood estimation algorithm that ensures the feasibility of risk estimates of the LEXPIT model and describe procedures for defining the feasible region of the parameter space, judging convergence, and evaluating boundary cases. Simulations demonstrate that the methodology is computationally robust and yields feasible, consistent estimators. We applied the LEXPIT model to estimate the absolute 5-year risk of cervical precancer or cancer associated with different Pap and human papillomavirus test results in 167,171 women undergoing screening at Kaiser Permanente Northern California. The LEXPIT model found an increased risk due to abnormal Pap test in human papillomavirus-negative that was not detected with logistic regression. Our R package blm provides free and easy-to-use software for fitting the LEXPIT model.

Risk of cervical precancer and cancer in women with cervical intraepithelial neoplasia grade 1 on endocervical curettage.

OBJECTIVE: This study aimed to characterize the 24-month risk of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) and grade 3 or worse (CIN 3+) in women with low-risk cytological finding and CIN 1 on endocervical curettage (ECC). MATERIALS AND METHODS: Cervical screening tests and cervical biopsy results from Kaiser Permanente Northern California were reviewed for years 2004 to 2008. Women with index cytological result of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion who underwent excisional procedure within 24 months of CIN 1 diagnosis were grouped by ECC status. A third cohort comprised women with ECC-CIN 1 followed up without excisional procedure. The 24-month cumulative incidence of CIN 2+ and CIN 3+ was calculated for each cohort. RESULTS: Excisional procedures were performed in 224 women; 54 had ECC-CIN 1 with ectocervical biopsy CIN 1 or less, and 170 had ectocervical CIN 1 with negative ECC finding. The 24-month risk of CIN 2+ was lower in the ECC-CIN 1 cohort compared with the ECC-negative (ectocervical CIN 1) cohort (24.1 vs 44.7%, p = .018) and nonsignificantly lower for CIN 3+ (7.4% vs 14.1%, p = .23). Among 203 women with ECC-CIN 1 followed up without excisional procedure but with follow-up ECC at a median of 21.7 months from index ECC, CIN 2 was found in 21 (10.3%, 95% CI = 6.7%-15.6%), and CIN 3 was found in 3 (1.5%, 95% CI = 0.4%-4.6%). CONCLUSIONS: A diagnosis of CIN 1 on ECC preceded by atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion does not increase the risk of CIN 2+ compared with women with ectocervical CIN 1 and negative ECC. The risk of CIN 2+ in women followed up without excisional procedure is sufficiently low that it is reasonable to offer conservative management similar to that for ectocervical CIN 1.