Comparing the performance of 2 human papillomavirus assays for a new use indication: a real-world evidence-based evaluation in the United States.

BACKGROUND: The US Food and Drug Administration supports innovations to facilitate new indications for high-risk human papillomavirus testing. This report describes the retrospective testing of stored specimens and analysis of existing data to efficiently and cost-effectively support a new indication for the Onclarity human papillomavirus assay (Becton, Dickinson and Company, BD Life Sciences - Integrated Diagnostic Solutions, Sparks, MD). The performance of this index test was compared with that of a predicate test, the cobas human papillomavirus assay (Roche Diagnostics, Indianapolis, IN). Both human papillomavirus assays are based on real-time polymerase chain reaction platforms that detect the presence of 14 high-risk human papillomavirus genotypes. The predicate assay reports human papillomavirus types 16 and 18 as individual results and the other 12 human papillomavirus genotypes as 1 pooled result. The index assay reports 9 independent results (human papillomavirus types 16, 18, 31, 33/58, 35/39/68, 45, 51, 52, and 56/59/66). Both the index and predicate assays are approved by the Food and Drug Administration for cervical cancer screening, but at the time that this study was initiated, the index human papillomavirus assay was not approved for use with cervical specimens collected in PreservCyt (Hologic, Inc, San Diego, CA) liquid-based cytology media. OBJECTIVE: The performance of the index human papillomavirus assay was compared with that of the predicate human papillomavirus assay for the detection of cervical intraepithelial neoplasia grades 2 or greater and 3 or greater (≥CIN2 or ≥CIN3) using PreservCyt liquid-based cytology specimens collected from women aged 21 to 65 years. In addition, the ability of the index test's extended genotyping to stratify ≥CIN2 and ≥CIN3 risks, using these specimens, was evaluated. STUDY DESIGN: The New Mexico HPV Pap Registry was used to select an age- and cytology-stratified random sample of 19,879 women undergoing opportunistic cervical screening and follow-up in routine clinical practice across New Mexico. A subset (n = 4820) of PreservCyt specimens was selected from 19,879 women for paired testing by the index and predicate human papillomavirus assays within age and cytology strata and included women with or without cervical biopsy follow-up. Point estimate differences and ratios were calculated for cervical disease detection and positivity rates, respectively, with 95% confidence intervals to determine statistical significance. The cumulative risk of ≥CIN2 or ≥CIN3, with up to 5-year follow-up, was estimated for the index assay using Kaplan-Meier methods. RESULTS: The 5-year cumulative ≥CIN3 detection rates were 5.6% for the index assay and 4.6% for the predicate assay (difference, 1.0%; 95% confidence interval, 0.5%-1.5%). The ≥CIN3 positivity rates within <1 year were 95.3% for the index assay and 94.5% for the predicate assay (ratio, 1.01; 95% confidence interval, 0.98-1.06). The ≥CIN3 cumulative positivity rates for the index and predicate assays were also similar at 5 years. Among cases of ≥CIN3, the positive agreement rates between the index and predicate assays for human papillomavirus types 16 and 18 were 100.0% (95% confidence interval, 95.0%-100.0%) and 90.9% (95% confidence interval, 62.3%-98.4%), respectively. Human papillomavirus type 16 carried the highest ≥CIN2 or ≥CIN3 risk, followed by human papillomavirus types 18/31/33/58/52/45 and human papillomavirus types 35/56/59/51/56/59/66. CONCLUSION: The index and predicate human papillomavirus assays demonstrated equivalent performance, and extended human papillomavirus genotyping, using the index assay, provided effective ≥CIN2 and ≥CIN3 risk stratification, supporting a new indication for use of the index assay with PreservCyt.

Risk stratification of HPV-positive results using extended genotyping and cytology: Data from the baseline phase of the Onclarity trial.

BACKGROUND: Optimizing the balance between colposcopy referrals and the detection of high-grade cervical intraepithelial neoplasia (CIN) during cervical cancer screening requires robust triage strategies. We evaluated the performance of extended HPV genotyping (xGT), in combination with cytology triage, and compared it to previously published performance data for high-grade CIN detection by HPV16/18 primary screening in combination with p16/Ki-67 dual staining (DS). METHODS AND MATERIALS: The baseline phase of the Onclarity trial enrolled 33,858 individuals, yielding 2978 HPV-positive participants. Risk values for ≥CIN3 were determined for Onclarity result groupings corresponding to HPV16, not HPV16 but HPV18 or 31, not HPV16/18/31 but HPV33/58 or 52, not HPV16/18/31/33/58/52 but HPV35/39/68 or 45 or 51 or 56/59/66 across all cytology categories. Published data from the IMPACT trial for HPV16/18 plus DS was utilized as a comparator during ROC analyses. RESULTS: There were 163 ≥ CIN3 cases detected. The ≥CIN3 risk stratum hierarchy (% risk of ≥CIN3) that resulted from this analysis included: >LSIL (39.4%); HPV16, ≤LSIL (13.3%); HPV18/31, ≤LSIL (5.9%); HPV33/58/52/45, ASC-US/LSIL (2.4%); HPV33/58/52, NILM (2.1%); HPV35/39/68/51/56/59/66, ASC-US/LSIL (0.9%); and HPV45/35/39/68/51/56/59/66, NILM (0.6%). For ≥CIN3 ROC analysis, the optimal cutoff for sensitivity versus specificity was approximated between not HPV16 but HPV18 or 31, any cytology (≥CIN3 sensitivity = 85.9% and colposcopy-to- ≥ CIN3 = 7.4) and not HPV16/18/31 but HPV33/58/52, NILM (≥CIN3 sensitivity = 94.5% and colposcopy-to- ≥CIN3 = 10.8). HPV16/18 with DS triage showed a sensitivity of 94.3%, with a colposcopy-to- ≥ CIN3 ratio of 11.4. CONCLUSIONS: xGT performed similarly compared to HPV primary screening plus DS for detection of high-grade CIN. xGT provides results that stratify risk in a flexible and reliable manner for colposcopy risk thresholds set by different guidelines or organizations.

Detection of high-grade cervical neoplasia using extended genotyping: Performance data from the longitudinal phase of the Onclarity trial.

OBJECTIVES: The Onclarity cervical cancer screening trial was designed to establish the clinical validity of the Onclarity HPV assay for extended genotyping (xGT) during detection of high-grade cervical neoplasia grades 2 or 3 (≥CIN2 or ≥CIN3). Here, three-year follow up data is presented to evaluate the overall efficacy of these screening strategies, compared to the baseline data. METHODS: At baseline 29,513 women, ≥25 years, had evaluable cytology and valid high-risk HPV results. Women with atypical squamous cells-undetermined significance or worse cytology or a positive HPV test were referred for colposcopy/biopsy. Participants that did not reach the study end point (treatment for ≥CIN2) continued into the longitudinal phase that included the same protocol as baseline. RESULTS: The three-year cumulative incident risk (CIR) for ≥CIN3 in HPV-negative women was 0.15% [95%CI: 0.06, 0.26] and for HPV- and cytology-negative women was 0.12% [95% CI: 0.03,0.23]. HPV16 carried the highest baseline and three-year ≥CIN3 CIR, followed by HPV31 and HPV18. At least one year of genotype-specific persistence increased ≥CIN3 risk for xGT results compared to genotype non-persistence, HPV clearance, or new infection over the same time period. Risk-based screening with immediate colposcopy for HPV16/18/31 and further xGT triage resulted in better ≥CIN3 sensitivity (79.2% versus 72.3%; relative difference of 6.9 [95%CI: 3.3, 10.4]) and a lower colposcopy/≥CIN3 ratio (9.2 versus 11.2; relative difference of -1.9 [95%CI: -2.6, -1.3]) when compared to primary HPV16/18-based screening. CONCLUSIONS: An HPV-negative result offers the same assurance of no disease over three years of follow up as that offered by a negative co-testing result. xGT facilitates risk-based screening and persistence tracking and can help optimize disease detection during screening without excessive colposcopic procedures.

A pragmatic approach for dynamically incorporating predicate device data in prospective diagnostic test studies.

Clinical studies are generally required to characterize the accuracy of new diagnostic tests. In some cases, historical data are available from a predicate device, which is directly relevant to the new test. If this data can be appropriately incorporated into the new test study design, there is an opportunity to reduce the sample size and trial duration for the new test. One approach to achieve this is the Bayesian power prior method, which allows for the historical information to be down-weighted via a power parameter. We propose a dynamic method to calculate the power parameter based on first comparing the data between the historical and new data sources using a one-sided comparison, and second mapping the comparison probability through a scaled-Weibull discount function to tune the effective sample size borrowed. This pragmatic and conservative approach is embedded in an adaptive trial framework allowing for the trial to stop early for success. An example is presented for a new test developed to detect Methicillin-resistant Staphylococcus aureus present in the nasal carriage.

Large-Scale SARS-CoV-2 Antigen Testing With Real-World Specimens.

Real-world data are needed to establish SARS-CoV-2 rapid antigen testing (RAT) as an effective and reliable approach for SARS-CoV-2 screening. This study included 1,952,931 individuals who provided upper respiratory specimens during SARS-CoV-2 screening at CityMD urgent care locations in the New York metropolitan area from October 2020 to March 2021. Positive and negative results, as determined by the BD Veritor™ System for Rapid Detection of SARS-CoV-2 antigen (Veritor), were obtained for all individuals, with reflex reverse transcriptase-polymerase chain reaction (RT-PCR) testing performed on a case-by-case basis, per standard of care. Using verification bias adjustment, two alternative model assumptions were utilized for RAT results with missing reflex RT-PCR results. The worst antigen diagnostic performance estimates asserted that missing RT-PCR results would show a distribution similar to those RT-PCR results actually obtained, based on symptom category. The best antigen diagnostic performance estimates asserted that individuals without RT-PCR results had a clinical presentation consistent with RAT results, and, therefore, missing RT-PCR results would agree with RAT results. For patients with symptoms or high-risk exposure, 25.3% (n = 86,811/343,253) of RAT results were positive; vs. 3.4% (n = 53,046/1,559,733) positive for asymptomatic individuals without high-risk exposure. Reflex RT-PCR results were obtained from 46.3% (n = 158,836/343,253) and 13.8% (n = 215,708/1,559,733) of symptomatic and asymptomatic individuals, respectively. RT-PCR confirmed 94.4% (4,265/4,518) of positive and 90.6% (139,759/154,318) of negative RAT results in symptomatic individuals; and confirmed 83.4% (6,693/8,024) of positive and 95.3% (197,955/207,684) of negative RAT results in asymptomatic individuals. Applied assumptions for missing reflex RT-PCR results led to worst performance sensitivity estimates of 77.2 and 38.5% in the symptomatic and asymptomatic populations, respectively; assumptions for best performance estimates led to sensitivity values of 85.6 and 84.2%, respectively. Specificity values, regardless of assumptions or symptom category, ranged from 97.9-99.9%. At 10% SARS-CoV-2 prevalence, RAT positive predictive value was 86.9 and 99.0% for worst and best performance estimates across the total population, respectively; negative predictive values were >95% regardless of the applied assumption. Veritor test performance was consistent with that listed in the manufacturer instructions for use for symptomatic individuals. Real-world evidence should be gathered on RATs to support their efficacy as SARS-CoV-2 persists.

Factors that Influence the Reported Sensitivity of Rapid Antigen Testing for SARS-CoV-2.

Tests that detect the presence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antigen in clinical specimens from the upper respiratory tract can provide a rapid means of coronavirus disease 2019 (COVID-19) diagnosis and help identify individuals who may be infectious and should isolate to prevent SARS-CoV-2 transmission. This systematic review assesses the diagnostic accuracy of SARS-CoV-2 antigen detection in COVID-19 symptomatic and asymptomatic individuals compared to quantitative reverse transcription polymerase chain reaction (RT-qPCR) and summarizes antigen test sensitivity using meta-regression. In total, 83 studies were included that compared SARS-CoV-2 rapid antigen-based lateral flow testing (RALFT) to RT-qPCR for SARS-CoV-2. Generally, the quality of the evaluated studies was inconsistent; nevertheless, the overall sensitivity for RALFT was determined to be 75.0% (95% confidence interval: 71.0-78.0). Additionally, RALFT sensitivity was found to be higher for symptomatic vs. asymptomatic individuals and was higher for a symptomatic population within 7 days from symptom onset compared to a population with extended days of symptoms. Viral load was found to be the most important factor for determining SARS-CoV-2 antigen test sensitivity. Other design factors, such as specimen storage and anatomical collection type, also affect the performance of RALFT. RALFT and RT-qPCR testing both achieve high sensitivity when compared to SARS-CoV-2 viral culture.

Antigen-Based Testing but Not Real-Time Polymerase Chain Reaction Correlates With Severe Acute Respiratory Syndrome Coronavirus 2 Viral Culture.

BACKGROUND: Individuals can test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by molecular assays following the resolution of their clinical disease. Recent studies indicate that SARS-CoV-2 antigen-based tests are likely to be positive early in the disease course, when there is an increased likelihood of high levels of infectious virus. METHODS: Upper respiratory specimens from 251 participants with coronavirus disease 2019 symptoms (≤7 days from symptom onset) were prospectively collected and tested with a lateral flow antigen test and a real-time polymerase chain reaction (rt-PCR) assay for detection of SARS-CoV-2. Specimens from a subset of the study specimens were utilized to determine the presence of infectious virus in the VeroE6TMPRSS2 cell culture model. RESULTS: The antigen test demonstrated a higher positive predictive value (90%) than rt-PCR (70%) when compared to culture-positive results. The positive percentage agreement for detection of infectious virus for the antigen test was similar to rt-PCR when compared to culture results. CONCLUSIONS: The correlation between SARS-CoV-2 antigen and SARS-CoV-2 culture positivity represents a significant advancement in determining the risk for potential transmissibility beyond that which can be achieved by detection of SARS-CoV-2 genomic RNA. SARS-CoV-2 antigen testing can facilitate low-cost, scalable, and rapid time-to-result, while providing good risk determination of those who are likely harboring infectious virus, compared to rt-PCR.

Risk detection for high-grade cervical disease using Onclarity HPV extended genotyping in women, ≥21 years of age, with ASC-US or LSIL cytology.

OBJECTIVES: There is growing interest in using human papillomavirus (HPV) genotyping as a risk-based triage approach for women with atypical squamous cells-undetermined significance (ASC-US) and low-grade squamous intraepithelial lesions (LSIL) cytology. METHODS: This analysis includes 2807 subjects with ASC-US or LSIL cytology, ≥21 years, from the baseline phase of the Onclarity HPV trial. All women were referred to colposcopy/biopsy. Hierarchical-ranked prevalence and risk values, associated with high-grade cervical disease, were calculated based on extended genotyping. RESULTS: HPV 16 carried the highest risk for cervical intraepithelial neoplasia grade 2 or worse (≥CIN2) in both the ASC-US and LSIL populations. Risk of ≥CIN3 and ≥CIN2 associated with the other 13 genotypes varied somewhat for women with ASC-US and LSIL, however, HPV 31, 18, 33/58, 51 and 52 appear to comprise an intermediate risk band. Risk associated with HPV 35/39/68, 45, and 56/59/66, in either cytology population, was relatively low and beneath the benchmark threshold risk for immediate colposcopy. Restricting the analysis to women 21-24 years, ≥25 years, or ≥30 years produced similar results. CONCLUSIONS: HPV genotyping identified multiple risk bands for ≥CIN3 and ≥CIN2 in the ≥21 year-old ASC-US and LSIL populations. These results support a 1-year follow-up period to preclude immediate colposcopy for ASC-US or LSIL women positive for the lowest-risk HPV genotypes.

Bayesian analysis of baseline risk of CIN2 and ≥CIN3 by HPV genotype in a European referral cohort.

Whereas HPV16 and HPV18 have been the focus in current risk-based cervical cancer screening algorithms using HPV genotype information, mounting evidence suggests that oncogenic HPV types such as HPV31, 33, 52 and 58 pose a ≥CIN3 risk equivalent to or greater than that of HPV18, and the combined risk of HPV31 and HPV33 rivals even HPV16 in women above 30 years of age. Here, we evaluate the baseline risk of CIN2 and CIN3 by genotype in a colposcopy referral population from Denmark and Italy. In total, 655 women were enrolled upon a referral to colposcopy after a positive screening sample. All samples were HPV analyzed using Onclarity HPV assay with extended genotyping and combined with the histology outcomes, a Bayesian probability modeling was used to determine the risk per genotype assessed. The combined data for this referral population showed that the ≥CIN2 risk of HPV16 was 69.1%, HPV31 at 63.3%, HPV33/58 at 52.7%, HPV18 at 46.6% and HPV52 at 40.8%. For ≥CIN3, the risks were 44.3%, 38.5%, 36.8%, 30.9% and 16.8% for HPV16, HPV31, HPV18, HPV33/58 and HPV52, respectively, indicating that the baseline risk of disease arising from HPV16 is, not surprisingly, the highest among the oncogenic HPV genotypes. We find that the HPV genotype-specific ≥CIN2 and ≥CIN3 risk-patterns are so distinct that, for example, 35/39/68 and 56/59/66 should be considered only for low intensive follow-up, thereby proposing active use of this information in triage strategies for screening HPV-positive women.

HPV infections and cytologic abnormalities in vaccinated women 21-34 years of age: Results from the baseline phase of the Onclarity trial.

OBJECTIVES: Countries with school-based human papillomavirus (HPV) vaccination have seen significant reductions in vaccine-targeted HPV infections, cytologic abnormalities, and high-grade cervical intraepithelial neoplasia (≥CIN2). However, the impact of HPV vaccination in the United States (where vaccination is largely opportunistic) may be less due to lower coverage rates and vaccination in patients at ages beyond the recommended routine vaccination age. METHODS: The Onclarity trial enrolled 33,858 subjects ≥21 years who were screened with cytology and the BD Onclarity HPV Assay. HPV positive women or those with cytologic abnormalities underwent colposcopy and biopsy. The prevalence of HPV, cytologic abnormalities, and ≥CIN2 was compared in a subset of 14,153, vaccinated and unvaccinated women, 21-34 years. Results were compared by vaccination status; Mantel-Haenszel analysis was performed to determine the association between vaccination status and prevalence, adjusting for age. RESULTS: The prevalence of overall HPV, HPV16, 18, 31, and 33/58 were all lower in vaccinated women for each age group; a significant difference (p < 0.001) was observed in vaccinated women for all ages combined. Cytologic low-grade squamous intraepithelial lesion (LSIL) or worse was lower in vaccinated women (p = 0.021), as was ≥CIN2 prevalence associated with HPV 16 or 18 (p = 0.011). CONCLUSIONS: Women with a prior history of HPV vaccination have a lower prevalence of any high-risk HPV, HPV 16, 18, 31, and 33/58; a cytology result of ≥LSIL, and ≥CIN2 associated with HPV 16/18 compared to unvaccinated women. A lower HPV prevalence in older, vaccinated women suggests that "catch-up" vaccination provides benefit.

Stratified risk of high-grade cervical disease using onclarity HPV extended genotyping in women, ≥25 years of age, with NILM cytology.

OBJECTIVES: Increasing evidence suggests that extended human papillomavirus (HPV) genotyping (beyond 16/18) is effective for risk stratification in women with normal cytology. This report provides extended genotyping results, using the BD Onclarity HPV Assay, for individual genotypes HPV16, 18, 31, 45, 51, and 52 ̶ and three pooled genotype results for HPV33/58, 35/39/68, and 56/59/66. METHODS: 27,037 women with normal cytology, ≥25 years, were enrolled into the Onclarity HPV trial during routine screening. Women positive for any HPV genotype were referred to colposcopy/biopsy. Hierarchical-ranked prevalence and risk values, associated with cervical intraepithelial neoplasia, grade 2 or worse (≥CIN2) or ≥CIN3, were calculated based on extended genotyping results. RESULTS: HPV 16 and 31 carried the highest risk for ≥CIN2 (11.6% and 12.1%, respectively) and ≥CIN3 (8.1% and 7.5%, respectively); these genotypes were the most prevalent in both ≥CIN2 (29.6% and 19.3%, respectively) and ≥CIN3 (43.7% and 22.5%, respectively). Of the other 12 genotypes, HPV 18, 33/58, and 52 comprised an intermediate risk band (≥CIN2 risk range: 4.9-6.8%; ≥CIN3 risk range: 3.9-5.0%). Genotypes 45, 51, 35/39/68, and 56/59/66 constituted the lowest risk band for both disease grades (≥CIN2 value risk range: 1.7-3.0%; ≥CIN3 value risk range: 1.2-3.6%). CONCLUSIONS: Extended genotyping stratifies risk for ≥CIN2/3 in the ≥25 year-old, normal cytology population. While baseline HPV 16/31 values exceeded the risk threshold for colposcopy referral, the management of women with normal cytology who were positive for the intermediate- or lower-risk genotypes may evolve based on refined risk estimates as well as clinical factors.

HPV Testing With 16, 18, and 45 Genotyping Stratifies Cancer Risk for Women With Normal Cytology.

OBJECTIVES: To determine the BD Onclarity human papillomavirus (HPV) assay performance and risk values for cervical intraepithelial neoplasia grade 2 (CIN2) or higher and cervical intraepithelial neoplasia grade 3 (CIN3) or higher during Papanicolaou/HPV cotesting in a negative for intraepithelial lesions or malignancies (NILM) population. METHODS: In total, 22,383 of the 33,858 enrolled women were 30 years or older with NILM cytology. HPV+ and a subset of HPV- patients (3,219/33,858 combined; 9.5%) were referred to colposcopy/biopsy. RESULTS: Overall, 7.9% of women were Onclarity positive; HPV 16 had the highest prevalence (1.5%). Verification bias-adjusted (VBA) CIN2 or higher and CIN3 or higher prevalences were 0.9% and 0.3%, respectively. Onclarity had VBA CIN2 or higher (44.1%) and CIN3 or higher (69.5%) sensitivities, as well as CIN2 or higher (92.4%) and CIN3 or higher (92.3%) specificities-all similar to Hybrid Capture 2. HPV 16, 18, 45, and the other 11 genotypes had CIN3 or higher risks of 6.9%, 2.6%, 1.1%, and 2.2%, respectively. CONCLUSIONS: Onclarity is clinically validated for cotesting in NILM women. Genotyping actionably stratifies women at greater CIN3 or higher risk.

Detection of Cervical Neoplasia by Human Papillomavirus Testing in an Atypical Squamous Cells-Undetermined Significance Population: Results of the Becton Dickinson Onclarity Trial.

Objectives: To determine clinical utility of Onclarity human papillomavirus (HPV) assay for atypical squamous cells-undetermined significance (ASC-US) triage, and the value of HPV genotyping within ASC-US. Methods: Women (n = 33,858; 21 years or older) had HPV testing using Onclarity and Hybrid Capture 2 (HC2). ASC-US individuals (n = 1,960, 5.8%) were referred to colposcopy. Results: Of ASC-US, 39.1% were HPV positive by Onclarity; HPV 16 was the most prevalent genotype (7.4%). Cervical intraepithelial neoplasia grade 2 (CIN 2) and CIN 3+ prevalences were 4.4% and 2.2%, respectively. Onclarity had sensitivity for CIN 2+ (85.7%) and CIN 3+ (91.4%), and specificities for CIN 2+ (64.1%) and CIN 3+ (62.0%), similar to HC2. Risks for CIN 3+ were 16.1%, 2.8%, 2.5%, and 2.7% with HPV 16, 18, 45, and 11 other genotypes, respectively. Conclusions: Onclarity is clinically validated for ASC-US triage. Through risk stratification, genotyping could help identify women at highest risk for CIN 3+.

Risk of Cervical Intraepithelial Neoplasia 2 or Worse by Cytology, Human Papillomavirus 16/18, and Colposcopy Impression: A Systematic Review and Meta-analysis.

OBJECTIVE: To calculate pooled risk estimates for combinations of cytology result, human papillomavirus (HPV) 16/18 genotype and colposcopy impression to provide a basis for risk-stratified colposcopy and biopsy practice. DATA SOURCE: A PubMed search was conducted on June 1, 2016, and a ClinicalTrials.gov search was conducted on June 9, 2018, using key words such as "uterine cervical neoplasms," "cervical cancer," "mass screening," "early detection of cancer," and "colposcopy." METHODS OF STUDY SELECTION: Eligible studies must have included colposcopic impression and either cytology results or HPV 16/18 partial genotype results as well as a histologic biopsy diagnosis from adult women. Manuscripts were reviewed for the following: cytology, HPV status, and colposcopy impression as well as age, number of women, and number of cervical intraepithelial neoplasia (CIN) 2, CIN 3, and cancer cases. Strata were defined by the various combinations of cytology, genotype, and colposcopic impression. TABULATION, INTEGRATION, AND RESULTS: Of 340 abstracts identified, nine were eligible for inclusion. Data were also obtained from three unpublished studies, two of which have since been published. We calculated the risk of CIN 2 or worse and CIN 3 or worse based on cytology, colposcopy, and HPV 16/18 test results. We found similar risk patterns across studies in the lowest risk groups such that risk estimates were similar despite different referral populations and study designs. Women with a normal colposcopy impression (no acetowhitening), less than high-grade squamous intraepithelial lesion cytology, and HPV 16/18-negative were at low risk of prevalent precancer. Women with at least two of the following: high-grade squamous intraepithelial lesion cytology, HPV16- or HPV18-positive, and high-grade colposcopic impression were at highest risk of prevalent precancer. CONCLUSION: Our results support a risk-based approach to colposcopy and biopsy with modifications of practice at the lowest and highest risk levels.

The Onclarity Human Papillomavirus Trial: Design, methods, and baseline results.

OBJECTIVES: The baseline phase of the Onclarity trial was conducted to determine the screening performance of the Onclarity human papillomavirus (HPV) assay for detecting cervical cancer and precancer (≥CIN2) during triage of women ≥21 years with ASC-US cytology, as an adjunct test in women ≥30 years with normal cytology and for primary screening (HPV alone) in women ≥25 years. METHODS: 33,858 women ≥21 years were enrolled during routine clinic visits. All women with abnormal cytology, women ≥25 years that were high-risk HPV positive, and a random subset of women ≥25 years, negative by cytology and for HPV, were referred for colposcopy and cervical biopsy. Verification bias adjustment with 95% confidence intervals was applied. RESULTS: ASC-US prevalence was 5.8%. The overall HPV prevalence was 14.7%; for HPV 16, 18, and the 12 other HPV types it was 2.7%, 0.8%, and 11.2%, respectively. The prevalence of ASC-US and HPV was inversely proportional with age. The verification bias adjusted prevalence of ≥CIN2 and ≥CIN3 was 1.8% and 0.8%, respectively. Overall, five cases of cervical cancer were identified (all were HPV positive). The odds ratios associated with any HPV positive genotype, or with individual genotypes HPV 16, HPV 18, and HPV 31, for ≥CIN3, were statistically significant when compared to negative histology (p < 0.0001 for all). CONCLUSIONS: This report provides demographic information, cytology findings, HPV genotype information, and histopathology for participants in the baseline phase of this trial and offers further evidence to support genotype-specific screening for cervical cancer and precancer. Clinical Trial Registry URL:https://clinicaltrials.gov/ct2/show/NCT01944722.

Safety and efficacy of insulin therapy delivered via a 4mm pen needle in obese patients with diabetes.

OBJECTIVE: To determine whether insulin delivered via a 4-mm × 32-gauge pen needle (PN) provides equivalent glycemic control as 8-mm × 31-gauge and 12.7-mm × 29-gauge PNs in obese (body mass index ≥30) patients with diabetes. PATIENTS AND METHODS: This prospective, multicenter, randomized, open-label, 2-period, crossover, equivalence, home-based study was conducted from October 26, 2010, through May 31, 2012. After a 3-week wash-in period, eligible patients aged 18 to 80 years with a hemoglobin A1c (HbA1c) level of 5.5% to 9.5% (37-80 mmol/mol) were randomized to compare either 4- vs 8-mm PNs or 4- vs 12.7-mm PNs, using each of the 2 assigned PNs for 12 weeks in random order. The primary outcome was change in HbA1c level, with equivalence limits of ±0.4%. RESULTS: The 274 patients randomized (mean ± SD age, 56.7±11.0 years) had a mean ± SD body mass index of 37.0±6.1 (range, 29.1-59.9) and took up to 350 U of insulin daily; 226 patients were included in the modified intention-to-treat analysis. Mean (95% CI) changes in HbA1c levels with the 4-mm PN were -0.08% (-0.21 to 0.06) and -0.10% (-0.19 to 0.00) vs the 8- and 12.7-mm PNs, respectively, within equivalence margins. The 4-mm PN was less painful than the larger PNs (P<.05), with similar leakage rates reported (4.1%-4.3%). Patients preferred the 4-mm PN over the 12.7-mm PN (P<.05) but not significantly vs the 8-mm PN. There were no differences between PNs in insulin doses and hypoglycemic or hyperglycemic adverse event rates. CONCLUSION: The 4-mm × 32-gauge PN provides equivalent glycemic control as 8- and 12.7-mm PNs in obese patients with diabetes, with less pain and no increase in leakage. Shorter PNs should be considered in all insulin-requiring patients with diabetes, including those who are obese. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01231984.

Evaluation of a new safety peripheral IV catheter designed to reduce mucocutaneous blood exposure.

OBJECTIVES: We evaluated performance and clinical acceptability of a new peripheral intravenous catheter (PIVC) designed to reduce blood exposure. METHODS: A two phased, unblinded, randomized controlled trial was conducted at a clinical research center in New Jersey, USA. In Phase 1, clinicians were asked to evaluate two devices: a PIVC with blood control (BD Insyte Autoguard * BC [Blood Control] Shielded IV Catheter), and a reference conventional PIVC (BD Insyte Autoguard Shielded IV Catheter). In Phase 2, clinicians compared two insertions of the investigational PIVC with blood control (PIVC-BC); one with venous compression and one without. The PIVC-BC was evaluated for superiority to the conventional PIVC with regard to blood exposure and for equivalence in general performance characteristics. RESULTS: Seventy-eight clinicians (mean age: 41.4 years; 89.7% female) and 234 healthy volunteers (mean age: 40.2 years; 61.5% female) were enrolled. Blood leakage occurred significantly more in the conventional PIVC group (39.1%) as compared to the PIVC-BC group (2.0%) (difference: 37.1% [95% CI: 28.8%; 45.15%]). Blood leakage rates for the PIVC-BC with or without use of venous compression were similar, 2.6% and 1.3% respectively (difference: 1.3% [95% CI: -7.8%; 4.7%]). A total of 98.7% of clinicians rated the PIVC-BC as clinically acceptable compared to 89.6% with the reference PIVC (difference: -9.1; 95% CI: -18; -1.5%) and 98.7% agreed it replaced the need for venous compression during catheter insertion (95% CI: 92.8%; 100%). Although the inability to blind clinicians to the investigational product was a potential source of bias, this was unlikely to affect assessments of observed blood leakage. CONCLUSIONS: The PIVC with blood control demonstrated reduced blood leakage during insertion and was rated no different for clinical acceptability and insertion performance compared to the conventional PIVC. Clinicians agreed that the new design replaced the need for venous compression to control blood flow during IV catheter insertion.

Evaluation of a new disposable silicon limbal relaxing incision knife by experienced users.

BACKGROUND: Previous research has suggested that the silicon BD Atomic Edge knife has superior performance characteristics when compared to a metal knife and performance similar to diamond knife when making various incisions. This study was designed to determine whether a silicon accurate depth knife has equivalent performance characteristics when compared to a diamond limbal relaxing incision (LRI) knife and superior performance characteristics when compared to a steel accurate depth knife when creating limbal relaxing incision. METHODS: Sixty-five ophthalmic surgeons with limbal relaxing incision experience created limbal relaxing incisions in ex-vivo porcine eyes with silicon and steel accurate depth knives and diamond LRI knives. The ophthalmic surgeons rated multiple performance characteristics of the knives on Visual Analog Scales. RESULTS: The observed differences between the silicon knife and diamond knife were found to be insignificant. The mean ratio between the performance of the silicon knife and the diamond knife was shown to be greater than 90% (with 95% confidence). The silicon knife's mean performance was significantly higher than the performance of the steel knife for all characteristics. (p-value < .05) CONCLUSIONS: For experienced users, the silicon accurate depth knife was found to be equivalent in performance to the diamond LRI knife and superior to the steel accurate depth knife when making limbal relaxing incisions in ex vivo porcine eyes. Disposable silicon LRI knives may be an alternative to diamond LRI knives.