Oral co‐infection with multiple alpha‐human papillomavirus and head and neck cancer risk

Abstract In Canada, the incidence of human papillomavirus (HPV)‐related head and neck cancer (HNC) is increasing. The role of multiple oral HPV infections in HNC etiology remains unclear, and evidence of HPV vaccination's effectiveness in reducing HNC incidence is limited. We investigated oral HPV co‐infection patterns, estimated the association between multiple oral HPV infections and HNC risk, and the effect of eliminating vaccine‐targeted HPV genotypes on HNC incidence. We used data from a case–control study with 460 incident HNC cases and 458 frequency‐matched controls recruited from four Montreal hospitals. In‐person interviews gathered life course exposure data, and exfoliated mouth and cancer site cells were analyzed for α‐HPV genotypes using PCR. We assessed co‐infecting α‐HPV genotypes' independence using a Poisson model and estimated the association between multiple oral α‐HPV infections and HNC risk using logistic regression. We also emulated a target trial, using targeted maximum likelihood estimation to evaluate the potential treatment effect of HPV vaccination on HNC. Among HPV‐positive individuals (164 cases, 61 controls), 34.76% of cases and 31.15% of controls had multiple oral α‐HPV infections. The observed distribution differed from expected under a mutually independent model of infection. Multiple α‐HPV infections increased HNC risk [OR = 4.66; 95%CI: 2.59, 8.76]. In the entire population [average treatment effect = −0.007, 95%CI; −0.008, −0.005] and among individuals without vaccine‐targeted HPV genotypes [average treatment effect on the treated = −0.04, 95%CI; −0.05, −0.03], HNC risk decreased. In conclusion, multiple oral α‐HPV infections are common and increase HNC risk. Conversely, HPV vaccination holds promise in reducing HNC incidence.