Cosette M Wheeler

HPV vaccine impact: genotype-specific changes in cervical pre-cancer share similarities with changes in cervical screening cytology

Abstract Background After human papillomavirus (HPV) vaccine introduction, declines in the prevalence of HPV vaccine types have been observed in screening cytology, but data from the United States describing HPV type-specific changes in cervical intraepithelial neoplasia (CIN) grades 2-3 and adenocarcinoma in situ (CIN2/CIN3/AIS) are limited. Methods A statewide sample of individuals with cervical biopsies was selected for broad-spectrum HPV genotyping. CIN2/CIN3/AIS incidence and prevalence were calculated for type-specific high-risk HPV (hrHPV) among individuals aged 15-29 years. Weighted incidence rate ratios (IRR) and relative differences in prevalence (RDP) were computed to compare 3 time periods: 2006-2009 (Cohort 1 [C1], n = 4121), 2012-2015 (C2, n = 2194), and 2015-2018 (C3, n = 1481). Results When comparing C1 vs C3 among those aged 21-25 years, statistically significant reductions in hrHPV type-specific CIN2/CIN3/AIS incidence were observed for HPV16, HPV18, HPV31, and HPV33, with corresponding IRRs of 0.4 (95% confidence interval [95% CI] = 0.3 to 0.4), 0.3 (95% CI = 0.1 to 0.7), 0.6 (95% CI = 0.5 to 0.9), and 0.4 (95% CI = 0.1 to 0.8), respectively. The RDP comparing C1 vs C3 for HPV16/18-positive CIN2/CIN3/AIS was -43.8% (P < .001). When excluding HPV16/18 or HPV16/18/31/33 from all hrHPV types, the RDP was +56.6% and +92.5% (P < .001), respectively. Conclusions hrHPV type-specific CIN2/CIN3/AIS incidence decreased with statistical significance for vaccine types HPV16/18 and for HPV31 and HPV33. Although the HPV vaccine is highly beneficial and a top priority for preventing HPV-related cancer, the long-term vaccine impact in cohorts receiving the 4-valent HPV vaccine requires continued follow-up to assess genotype-specific distributions in the remaining CIN2+ lesions and cancers.

Human papillomavirus genotype-specific prevalence and infection risks: a 10-year population-based study from the United States

Abstract Background Various studies have reported on the impact of human papillomavirus (HPV) vaccines. Here we present the largest population-based investigation of genotype-specific distributions over the decade following implementation of the quadrivalent HPV vaccine (HPV-6/11/16/18) in the United States. Methods Liquid-based cervical cytology samples from individuals aged 15-30 years undergoing cervical screening throughout New Mexico were tested by broad-spectrum HPV genotyping. Weighted relative differences in HPV type-specific prevalence and 95% confidence intervals (CIs) were calculated by comparing individuals screened between 2007 and 2009 (n = 95 915) with individuals screened between 2013 and 2016 (n = 103 371). Weighted logistic regression was used to estimate relative risk of type-specific HPV infections. Tests of significance were 2-sided. Results Genotype-specific prevalence fell with statistical signficance for HPV-16 (relative difference = ‒52.6%, 95% CI = ‒56.9 to ‒48.3), HPV-18 (relative difference = ‒62.1%, 95% CI = ‒68.5 to ‒55.8), HPV-31 (relative difference = ‒34.2%, 95% CI = ‒42.1 to ‒26.3), and HPV-33 (relative difference = ‒31.8%, 95% CI = ‒48.4 to ‒15.1). The relative difference increased for other carcinogenic HPV types by 19.5% (95% CI = 14.3 to 24.6) when excluding HPV-16/18. Large reductions in HPV-6/11 relative differences were observed, but overall, noncarcinogenic, nonvaccine types increased. Comparing female individuals born in 1996 with female individuals born in 1989, risk of infection with HPV-6, 11, 16, and 18 decreased by 80.0% among individuals aged 21-25 years. High-grade squamous intraepithelial lesions or worse decreased by 49.4% when extending the evaluation from 2007 to 2018. Conclusion The incidence of high-grade squamous intraepithelial lesions or worse is decreasing, with large reductions in the prevalence of quadrivalent HPV vaccine types and nonvaccine types HPV-31 and HPV-33, reflecting vaccine cross-protection. Increases in nonvaccine HPV genotypes may attenuate anticipated reductions in HPV-related abnormalities, including cancers, but the benefits of HPV vaccination remain substantial.

Promise and Perils of Primary HPV Testing

Abstract Cervical cancer screening has reduced morbidity and mortality in many countries, but efforts to optimize screening modalities and schedules are ongoing. Using data from a randomized trial conducted in British Columbia, Canada, in conjunction with a provincial screening registry, Gottschlich and colleagues demonstrated that the estimated risk for precancerous disease (cervical intraepithelial neoplasia grades 2 or worse) at 8 years following a negative human papillomavirus (HPV) test was similar to the current standard of care (Pap testing after 3 years). The study supports extending screening intervals for those with a negative HPV test beyond currently recommended 5-year intervals. In an ideal world, the resources saved through less frequent routine cervical screening could be redirected to increasing screening uptake and follow-up of abnormalities to improve equity in cervical cancer prevention. However, implementation of extending screening intervals remains less than straightforward in settings with fragmented healthcare systems that lack information systems to support patient call/recall, such as the United States. To achieve the full promise of primary HPV testing, stakeholders at every level must commit to identifying and addressing the diverse spectrum of barriers that undergird existing inequities in care access, appropriately resource implementation strategies, and improve health information systems. See related article by Gottschlich et al., p. 904

DNA methylation testing with S5 for triage of high‐risk HPV positive women

AbstractMethylation of host and viral genes is promising for triage of women with high‐risk human papillomavirus infections (hrHPV). Using a population‐based sample of hrHPV positive women with cervical biopsies within 12 months after cervical screening, the clinical value of the S5 methylation classifier (S5), HPV genotyping and cytology were compared as potential triage tests, for outcomes of cervical intraepithelial neoplasia (CIN) grade 3 or greater (CIN3+), CIN2+ and CIN2, and the area under the curve (AUC) calculated. S5 scores increased with histopathology severity (Ptrend < .001). For CIN3+, the AUC was 0.780 suggesting S5 provides good discrimination between <CIN3 and CIN3+. AUCs were significant for all pairwise comparisons of <CIN2, CIN2 and CIN3+ (P < .001). The positive predictive value (PPV) of HPV16/18 genotyping for women with any abnormal cytology was greater than S5 (25.36% vs 20.87%, P = .005) for CIN3+, while sensitivity was substantially greater for S5 (83.33% vs 59.28%, P < .001). Restricting to women with abnormal cytology, but excluding those with high‐grade cytology, both S5 and HPV16/18 provided CIN3+ PPVs high enough to recommend colposcopy. Triage with S5 also appeared useful for hrHPV positive women negative for HPV16/18 (CIN3+ PPV: 7.33%, sensitivity: 57.52%). S5 provided increased sensitivity for CIN3+ compared to HPV16/18 genotyping for hrHPV positive women, overall and when restricted to women with abnormal cytology, suggesting S5 may improve colposcopy referral. S5 also has the ability to distinguish between <CIN2, CIN2 and CIN3+, a finding of importance for managing CIN2, given the complexity and uncertainty associated with this diagnosis.

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

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. 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. 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. 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. 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.