Epidemiologic Approach to Evaluate Potential for HPV Type Replacement Post-Vaccination

Background: Two vaccines prevent the HPV genotypes that cause the majority of cervical cancers. It is possible that the distribution of the other high-risk types will change following the elimination of these vaccine types, a phenomenon referred to as type-replacement (TR). Objectives: Using HPV DNA typing data, we addressed the potential for TR by: comparing the observed (O) versus expected (E) number of coinfections involving vaccine types with other HPV types, and evaluating whether infection with specific HPV types affects acquisition/clearance of others. Methods: Data came from the following studies: Ludwig-McGill (n=2462), HITCH (n=1038), McGill-Concordia (n=636), BCCR (n=1687), and CCCaST (n=10154). HPV DNA was assessed using PGMY/MY PCR protocols to permit genotyping of 37 genital types. For each pair combination we calculated the expected frequency of coinfection by assuming infections occur independently, and compared this with the observed frequency. We also constructed hierarchical regression models for each HPV vaccine type by including all other types as exposures. Kaplan-Meier curves and Cox proportional hazard models were used to evaluate sequential acquisition/clearance of HPV types according to presence/absence of vaccine-preventable types. Results: Multiple-type HPV infection was common across studies (range=0.26-0.65). The O/E ratio for most pair combinations was >1 and not significant, suggesting no interaction between HPV infections. For HPV 16, only type 52 was flagged as a candidate for replacement (O/E ratio<1; range=0.36-0.48). Results from other statistical approaches provided similar inference. Conclusions: HPV types generally do not compete during natural infection. Our analysis provides reassurance that TR is not expected post-vaccination.