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.
The first biomarker-based cervical cancer screening test, p16/Ki-67 dual-stained cytology (DS), has been clinically validated and approved in the United States for triage of women being screened for cervical cancer who test positive for high-risk human papillomavirus (hrHPV). The primary aim of this work is to evaluate the cost-effectiveness of DS triage after co-testing findings of positive non-16/18 HPV types and atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesions (LSIL) cytology. A payer-perspective Markov microsimulation model was developed to assess the impact of DS reflex testing. Each comparison simulated 12,250 screening-eligible women through health states defined by hrHPV status and genotype, cervical intraepithelial neoplasia (CIN) grades 1-3, invasive cervical cancer (ICC) by stage, and cancer-related or non-cancer death. Screening test performance data were from the IMPACT clinical validation trial. Transition probabilities were from population and natural history studies. Costs of baseline medical care, screening visits, tests, procedures, and ICC were included. DS reflex after co-testing was cost-effective with incremental cost-effectiveness ratios (ICER) per quality-adjusted-life-year (QALY) gained of $15,231 (95% CI $10,717-$25,400) compared to co-testing with hrHPV pooled primary and genotyped reflex testing, and $23,487 (95% CI $15,745-$46,175) compared to co-testing with hrHPV genotyping with no reflex test. Screening and medical costs and life-years increased, while ICC costs and risk of ICC death decreased. Incorporating DS reflex into co-testing cervical cancer screening algorithms is projected to be cost-effective.
<p>Supplemental Table S2 shows the distribution of patient attributes in the prevalent US population of women eligible for cervical cancer screening</p>
<p>Supplemental Table S3 shows the procedure codes, CMS fee schedule payments, and usage information used to develop cost inputs for screening visits, tests, and procedures</p>
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