Background A nonavalent human papillomavirus (HPV) vaccine has been licensed for use in women and men up to age 45 years in the United States. The cost-effectiveness of HPV vaccination for women and men aged 30 to 45 years in the context of cervical cancer screening practice was evaluated to inform national guidelines. Methods and findings We utilized 2 independent HPV microsimulation models to evaluate the cost-effectiveness of extending the upper age limit of HPV vaccination in women (from age 26 years) and men (from age 21 years) up to age 30, 35, 40, or 45 years. The models were empirically calibrated to reflect the burden of HPV and related cancers in the US population and used standardized inputs regarding historical and future vaccination uptake, vaccine efficacy, cervical cancer screening, and costs. Disease outcomes included cervical, anal, oropharyngeal, vulvar, vaginal, and penile cancers, as well as genital warts. Both models projected higher costs and greater health benefits as the upper age limit of HPV vaccination increased. Strategies of vaccinating females and males up to ages 30, 35, and 40 years were found to be less cost-effective than vaccinating up to age 45 years, which had an incremental cost-effectiveness ratio (ICER) greater than a commonly accepted upper threshold of 200,000perquality-adjustedlifeyear(QALY)gained.WhenincludingallHPV-relatedoutcomes,theICERforvaccinatinguptoage45yearsrangedfrom 315,700 to 440,600perQALYgained.Assumptionsregardingcervicalscreeningcompliance,vaccinecosts,andthenaturalhistoryofnoncervicalHPV-relatedcancershadmajorimpactsonthecost-effectivenessofthevaccinationstrategies.Keylimitationsofthestudywererelatedtouncertaintiesinthedatausedtoinformthemodels,includingthetimingofvaccineimpactonnoncervicalcancersandvaccineefficacyatolderages.ConclusionsOurresultsfrom2independentmodelssuggestthatHPVvaccinationforadultwomenandmenaged30to45yearsisunlikelytorepresentgoodvalueformoneyintheUS.
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