Optimal cervical cancer screening strategies for unvaccinated and HPV-vaccinated cohorts in the United States: a comprehensive comparative modeling analysis

Background: Adult women in the United States (US) currently comprise a mix of birth cohorts with different human papillomavirus (HPV) vaccination uptake and thus markedly different risks of cervical cancer, while cervical screening recommendations do not currently reflect these differences. We used comparative modeling to determine the optimal screening protocols for these cohorts. Methods: We used three independent models calibrated to US data to simulate three birth cohorts: unvaccinated females born in 1980, females born in 1993 (predominantly offered bivalent/quadrivalent HPV vaccines), and females born in 2003 (predominantly offered nonavalent HPV vaccine). We considered primary cytology, primary HPV testing, and co-testing, and varied the starting age (21-30 years) and screening frequency (three- to ten-yearly), resulting in 92 strategies. Strategies that were on the cost-effectiveness frontier for at least one model and were associated with incremental cost-effectiveness ratios between US$50,000 and US$200,000 per life-year gained were considered optimal; we compared health outcomes, colposcopies, and precancer treatments for these strategies to those estimated under current guidelines. Findings: For all three birth cohorts, optimal screening strategies involved primary HPV testing and decreasing the screening intervals, i.e., five-yearly from age 25 years for the unvaccinated birth cohort, eight-yearly from age 25 for the 1993 cohort, and 10-yearly from age 27 for the 2003 cohort. Interpretation: Primary HPV screening is the optimal approach regardless of vaccine protection exposure but US cervical cancer screening intervals should be extended for vaccinated cohorts to maintain cost-effectiveness. This would reduce harms while remaining more effective than current guidelines in pre-vaccine cohorts. Funding: US National Cancer Institute.