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A Prospective Study Showing Long-Term Infection with Human Papillomavirus 16 before the Development of Cervical Carcinoma in Situ¹

Department of Medical Epidemiology, Karolinska Institutet, 171 77 Stockholm, Sweden [N. Y., P. Sp., H-O. A.]; Department of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen, Denmark [M. M., P. Sö., M. F., P. K. A.]; Department of Genetics and Pathology, Uppsala University, 751 23 Uppsala, Sweden [A. J., M. G., P. M., J. P., U. G.]; Department of Epidemiology, Harvard University, Boston, Massachusetts 02115 [H-O. A.]

Human papillomavirus 16 (HPV16) is a predominant cause of cervical neoplasia. However, no population-based study with long-term follow-up has clarified the temporal relationship between HPV16 infection and occurrence of carcinoma in situ, or the importance of recurrent or persistent infection. This nested case-control study was carried out in a population-based cohort of women participating in cytological screening whose initial smear, taken in 1969–1995, was normal. During up to 26 years of follow-up, carcinoma in situ was diagnosed in 484 eligible women. Archival smears from these women were compared with smears from 619 individually matched controls. After DNA extraction, a highly sensitive PCR system was used to detect HPV16. Among case women, the prevalence of HPV16 positivity was 56% at the time of diagnosis. The relative risk of cervical carcinoma in situ increased from 3.6 (95% confidence interval, 1.2–11.0) 13 years before diagnosis to 11.1 (95% confidence interval, 5.5–22.2) 1 year before diagnosis. Having a positive smear at entry to the cohort increased risk >5-fold, whereas having persistent infection with HPV in two subsequent smears increased risk 30-fold. We estimated that among HPV16-positive women, the median incubation period from infection to carcinoma in situ was 7–12 years. We conclude that evidence of persistent and/or recurrent infection is associated with a drastically higher risk of cervical carcinoma in situ than occasional infection with HPV16.

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