Detection of human papillomavirus DNA in cytologically normal women and subsequent cervical squamous intraepithelial lesions

Background: Human papillomavirus (HPV) infection has been strongly associat ed with cervical carcinoma and its cytologic precursors, squamous intraepit helial lesions (SIL). We investigated the risk of SIL prospectively followi ng polymerase chain reaction (PCR)based DNA testing for a wide range of gen ital HPV types in a cohort of initially cytologically normal women, to clar ify the role of HPV in the etiology of SIL. Methods: Starting in April 1989 , 17 654 women who were receiving routine cytologic screening at Kaiser Per manente (Portland, OR) were followed for the development of incident SIL. D uring follow-up, 380 incident case patients and 1037 matched control subjec ts were eligible for this nested case-control study. Cervical lavages colle cted at enrollment and, later, at the time of case diagnosis (or the corres ponding time for selection of central subjects) were tested for HPV DNA usi ng a PCR-based method. The data were analyzed as contingency tables with tw o-sided P values or, for multivariable analyses, using odds ratios (ORs) wi th 95% confidence intervals (CLs). Results: In comparison with initially HP V-negative women, women who tested positive for HPV DNA at enrollment were 3.8 times (95% CI = 2.6-5.5) more likely to have low-grade SIL subsequently diagnosed for the first time during follow-up and 12.7 times more likely ( 95% CI = 6.2-25.9) to develop high-grade SIL. At the time of diagnosis, the cross-sectional association of HPV DNA and SIL was extremely strong (OR = 44.4 and 95% CI = 24.2-81.5 for low-grade SIL and OR = 67.1 and 95% CI = 19 .3-233.7 for high-grade SIL). HPV16 was the virus type most predictive of S IL, even low-grade SIL. Conclusions: These findings are consistent with the hypothesis that HPV infection is the primary cause of cervical neoplasia, Furthermore, they support HPV vaccine research to prevent cervical cancer a nd efforts to develop HPV DNA diagnostic tests.