Mark H Stoler

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.

Comparison of Hybribio-H13 and Hybrid Capture® 2 human papillomavirus tests for detection of CIN2+ and CIN3+

Introduction. Low-cost, accurate high-risk HPV tests are needed for cervical cancer screening in limited-resource settings.Objective. To compare the performance of the low-cost Hybribio-H13 test with the Hybrid Capture® 2 to detect cervical intraepithelial neoplasia grade 2 or 3 (CIN2 and CIN3).Materials and methods. Archived baseline samples tested by the Hybrid Capture® 2 from women of the ASCUS-COL trial, aged 20 to 69 years, with biopsy-colposcopy directed diagnosis of CIN2+ (n = 143), CIN3+ (n = 51), and < CIN2 (n = 632) were blindly tested by the Hybribio-H13 test.Results. The relative sensitivity of the Hybribio-H13 test versus the Hybrid Capture® 2 for detecting CIN2+ was 0.89 (90% CI = 0,80-0,98; NIT = 0,66), and for CIN3+ was 0,92 (90% CI = 0,85-0,98; NIT = 0,35). Relative specificity was 1.19 (90% CI = 1.05-1.33; NIT <0.00001). In the analysis restricted to women older than 30 years, the relative sensitivity of the Hybribio-H13 for CIN3+ was marginally below unity (ratio = 0.97; 90% CI = 0.95-0.99), and the specificity remained higher than the Hybrid Capture® 2 test.Conclusion. The Hybribio-H13 test was as specific as the Hybrid Capture® 2 for detecting CIN2+ or CIN3+ but less sensitive. Considering these results and the young age of the population recruited for screening because of ASCUS cytology, we suggest our results warrant the evaluation of the Hybribio-H13 for screening cervical cancer, especially in the evaluated population.

Approaches to triage optimization in HPV primary screening: Extended genotyping and p16/Ki‐67 dual‐stained cytology—Retrospective insights from ATHENA

The objective of our study was to assess the performance of different triage strategies for high‐risk human papillomavirus (hrHPV)‐positive results utilizing either extended genotyping or a p16/Ki‐67 dual‐stained cytology (DS) approach, with or without partial genotyping. A subset of women with hrHPV infections participating in the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study were analyzed to determine the number of cervical intraepithelial neoplasia grade 3 or worse (≥CIN3) cases detected, and the absolute risk for ≥CIN3 of each genotype. A clinical utility table was constructed to compare the impact of different triage strategies. In all, 2,339 women with single‐genotype hrHPV infections were identified. Among these were 171 ≥CIN3 cases. The U.S. Food and Drug Administration (FDA)‐approved algorithm (HPV16/18 positive, or 12‐other hrHPV positive and Pap positive, i.e., ≥ atypical squamous cells of undetermined significance) for primary HPV screening detected 132/171 (77.2%) ≥CIN3 cases and required 964 colposcopies (colposcopies per ≥CIN3 ratio: 7.3). An approach that uses DS instead of cytology in the FDA‐approved algorithm detected 147/171 (86.0%) ≥CIN3 cases, requiring 1,012 colposcopies (ratio: 6.9). Utilizing DS for triage of all hrHPV‐positive women identified 126/171 (73.7%) ≥CIN3 cases, requiring 640 colposcopies (ratio: 5.1). A strategy that detected HPV16/18/31/33/35+ captured 130/171 (76.0%) ≥CIN3 cases, requiring 1,025 colposcopies (ratio: 7.9). Inclusion of additional genotypes resulted in greater disease detection at the expense of higher colposcopy ratios. Substituting cytology with a DS triage approach improved disease detection and the colposcopy detection rate. Further reduction of colposcopy rates can be achieved by using DS without partial genotyping. Extended genotyping strategies can identify a comparable number of cases but requires an increased number of colposcopies.

Role of Methylation Test Triage in HPV Positive Women

The pathological results were used as the gold standard in this study and the investigators analyze the diagnostic value of six gene methylation status (ASTN1 DLX1, ITGA4, RXFP3, SOX17, ZNF671) in triaging high-risk human papillomavirus infection. The sensitivity and specificity of methylation test and cytology in the diagnosis of high-grade cervical lesions are compared in order to providing new methods and basis in improving the accuracy of cervical cancer screening.