A prospective study showing long-term infection with human papillomavirus 16 before the development of cervical carcinoma in situ

Human papillomavirus 16 (HPV16) is a predominant cause of cervical neoplasi a. However, no population-based study with long-term follow-up has clarifie d the temporal relationship between HPV16 infection and occurrence of carci noma in situ, or the importance of recurrent or persistent infection, This nested case-control study was carried out in a population-based cohort of w omen participating in cytological screening whose initial smear, taken in 1 969-1995, 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 ext raction, 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% c onfidence interval, 1.2-11.0) 13 years before diagnosis to 11.1 (95% confid ence interval, 5.5-22.2) 1 year before diagnosis. Having a positive smear a t entry to the cohort increased risk >5-fold, whereas having persistent inf ection with HPV in two subsequent smears increased risk 30-fold. We estimat ed that among HPV16-positive women, the median incubation period from infec tion to carcinoma in situ was 7-12 years. We conclude that evidence of pers istent and/or recurrent infection is associated with a drastically higher r isk of cervical carcinoma in situ than occasional infection with HPV16.