Evaluation of using composite HPV genotyping assay results to monitor human papillomavirus infection burden through simulation

BACKGROUND: Researchers often group various HPV types into composite measures based on vaccine subtypes, oncogenic potential, or phylogenetic position. Composite prevalence estimates based on PCR genotyping assay results have been calculated to assess HPV infection burden and to monitor HPV vaccine effectiveness. While prevention and intervention strategies can be made based on these prevalence estimates, the discussion on how well these prevalence estimates measure the true underlying infection burdens is limited. METHODS: A simulation study was conducted to evaluate accuracy of using composite genotyping assay results to monitor HPV infection burden. Data were generated based on mathematical algorithms with prespecified type-specific infection burdens, assay sensitivity, specificity, and correlations between various HPV types. Estimated-to-true prevalence rate ratios and percent reduction of vaccine types were calculated. RESULTS: When “true” underlying type-specific infection burdens were prespecified as the reported prevalence in U.S. and genotyping assay with sensitivity and specificity (0.95, 0.95) was used, estimated-to-true infection prevalence ratios were 2.35, 2.29, 2.18, and 1.46, for the composite measures with 2 high-risk vaccine, 4 vaccine, 14 high-risk and 37 HPV types, respectively. Estimated-to-true prevalence ratios increased when prespecified “true” underlying infection burdens or assay specificity declined. When prespecified “true” type-specific infections of HPV 6, 11, 16 and 18 were reduced by 50%, the composite prevalence estimate of 4 vaccine types only decreased by 17% which is much lower than 48% reduction in the prespecified “true” composite prevalence. CONCLUSIONS: Composite prevalence estimates calculated based on panels of genotyping assay results generally over-estimate the “true” underlying infection burdens and could under-estimate vaccine effectiveness. Analytical specificity of genotyping assay is as or more important than analytical sensitivity and should be considered in selecting assay to monitor HPV.