Prospective seroepidemiological study of human papillomavirus infection as risk factor for invasive cervical cancer

Background: Major risk factors for invasive cervical cancer include infection with human papillomavirus (HPV), infec-tion with other sexually transmitted pathogens (e.g., Chla-mydia trachomatis), and smoking. Since exposures to these risk factors can be related, the contribution of any single factor to cervical carcinogenesis has been difficult to assess. We conducted a prospective study to define the role of HPV infection in cervical carcinogenesis, with invasive cancer as an end point. Methods: A nested case–control study within a joint cohort of 700 000 Nordic subjects was performed. The 182 women who developed invasive cervical cancer during a mean follow-up of 5 years were matched with 538 control women on the basis of age and time of enrollment. Serum samples taken at enrollment were analyzed for evidence of tobacco use (i.e., cotinine levels); for antibodies against HPV types 16, 18, and 33; and for antibodies against C. tracho-matis. Relative risks (RRs) were estimated by use of condi-tional logistic regression. Results: Presence of antibodies against HPV in serum (seropositivity) was associated with an increased risk of cervical cancer, and adjustment for smok-ing and for C. trachomatis seropositivity did not affect this finding (RR = 2.4; 95 % confidence interval [CI] = 1.6–3.7). HPV16 seropositivity was associated primarily with an in-creased risk of squamous cell carcinoma (RR = 3.2; 95 % CI = 1.7–6.2). In contrast, risk associated with HPV18 seropos-itivity tended to be higher for cervical adenocarcinoma (RR = 3.4; 95 % CI = 0.8–14.9). In populations with a low preva-lence of antibodies against C. trachomatis, the HPV16-associated risk of cervical cancer was very high (RR = 11.8; 95 % CI = 3.7–37.0); in contrast, in populations with a high prevalence of antibodies against C. trachomatis, no excess risk was found. Conclusion: Past infection with HPV16 in-creases the risk of invasive cervical squamous cell carci-noma, most clearly seen in populations with a low prevalence of sexually transmitted diseases. [J Natl Cancer Inst 1997