A mediation analysis to investigate the mechanism underlying smoking and HPV re-acquisition

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Authors

• RC Eldridge
• M Pawlita
• L Wilson
• PE Castle
• T Waterboer
• PE Gravitt
• M Schiffman
• N Wentzensen

Abstract

Smoking may be implicated at different stages throughout the natural history of human papillomavirus (HPV)-associated cancers. Smoking is an established risk factor for progression of HPV infection to cervical neoplasia, but its role in HPV re-acquisition is less clear. Also unclear is smoking’s underlying mechanism for re-acquisition and progression. Our previous study found an inverse association between smoking and naturally acquired antibodies against HPV, suggesting an immune response mechanism. In vitro studies suggest that tobacco condensate can induce DNA damage in HPV-infected cervical cells, suggesting a more direct mechanism. Recent methodological advances in mediation analysis allow for estimation of mechanisms in epidemiologic data – decomposing an overall effect into separate mechanistic effects. Using a two-year follow-up study of women (n=1,978), we sought to estimate how smoking influences HPV-16 re-acquisition. We posit our causal model, and estimate the natural indirect effect (antibody mechanism) and natural direct effect (alternative mechanism) through mediation analysis. Compared to never smokers, current smokers had an increased odds of HPV infection by the antibody-mediated indirect effect (OR=1.24, 95% CI: 1.08, 1.60); the direct effect was not significant (OR=0.66, 95% CI: 0.34, 1.31). For women who smoke at least half a pack of cigarettes daily, the indirect effect was stronger (OR=1.62, 95% CI: 1.20, 2.31).This is the first analytic model to suggest that current smoking increases the risk of re-acquiring an HPV infection by reducing HPV antibody titers. The estimate appears dose-dependent, more harmful for women who smoke at least half a pack of cigarettes per day.

Scientific Focus Area: Epidemiology

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