Smoking and subsequent human papillomavirus infection: a mediation analysis

Abstract

Purpose

Smoking is an established risk factor for a human papillomavirus (HPV) infection advancing to cervical precancer and cancer, but its role earlier in the natural history is less clear. Smoking is inversely associated with possessing HPV antibodies from a past infection suggesting that smoking may influence acquiring subsequent infections.

Methods

In a cohort of 1976 U.S. women, we evaluate whether reduced antibodies to HPV-16 is a mechanism for smoking's role on acquiring a subsequent HPV-16 infection, through the analytic technique of causal mediation analysis. We posit a causal model and estimate two counterfactually defined effects: a smoking impaired antibody-mediated indirect effect and a nonmediated direct effect representing all other potential mechanisms of smoking.

Results

Compared to never smokers, current smokers had increased odds of HPV-16 infection by the antibody-mediated indirect effect (odds ratio [OR] = 1.29; 95% confidence interval [CI]: 1.11, 1.73); the estimated direct effect was very imprecise (OR = 0.57; 95% CI, 0.26–1.13). We observed a stronger estimated indirect effect among women who smoked at least half a pack of cigarettes daily (OR = 1.61, 95% CI, 1.27–2.15) than among women who smoked less than that threshold (OR = 1.09; 95% CI, 0.94–1.44).

Conclusions

This is the first study to directly test the mechanism underlying smoking as an HPV cofactor. The results support current smoking as a risk factor earlier in the natural history of HPV and are consistent with the hypothesis that smoking increases the risk of a subsequent infection by reducing immunity.

Introduction

Human papillomavirus (HPV) infections are commonly acquired shortly after sexual initiation and are the necessary cause of cervical carcinogenesis [1]. Most infections are cleared within 1–2 years, but some persist. Women with a persistent carcinogenic HPV infection are at risk of developing precancerous lesions that may progress to cervical cancer [1], [2]. Some infected women will develop antibodies, which could protect against a subsequent infection by that HPV type [3], [4], [5], [6].

Risk factors are associated with acquiring antibodies from an HPV infection. Greater sexual activity increases a woman's exposure to HPV and thus her opportunity to develop antibodies [7], [8]. Other factors, such as smoking, may impair a woman's antibody response [9], [10], [11]. For smoking, a diminished antibody response could be a consequence of an impaired immune system. Smoking affects both the cellular and humoral immune response; it can reduce cytokines, natural killer cells, and immunoglobulins [12]. Impairing the cellular response could lead to a persistent infection by inadequate clearance of HPV, while impairing the humoral response could lead to a subsequent infection by inadequate antibody protection. Despite smoking being associated with a lower natural antibody response, it is unclear whether it results in an increased risk of subsequent HPV infection. To directly test that causal mechanistic research question in human subjects requires an analytic technique called mediation analysis.

In a secondary analysis within a large clinical trial, we sought to evaluate the role of smoking and naturally acquired antibodies in subsequent HPV-16 infections. We posit a causal model of smoking, HPV antibodies, and HPV subsequent infection to estimate two causal pathways using mediation analysis: (1) a smoking impaired antibody-mediated pathway; and (2) an alternative nonmediated pathway representing all other potential mechanisms of smoking.