Persistent infection with human papillomavirus 16 or 18 is strongly linked with high-grade cervical disease

Abstract

We investigated the relationship between high-grade cervical disease (cervical intraepithelial neoplasia [CIN] 2, CIN3 or adenocarcinoma in situ) and persistent infection with HPV16 and/or HPV18 (HPV16/18) among 3970 women who received placebo in 3 clinical trials of a quadrivalent HPV vaccine. Statistical analysis (odds ratios, sensitivity, specificity, negative and positive predictive values, negative and positive likelihood ratios) showed that patients with a persistent infection with HPV16/18 had a much greater risk of HPV16/18-related high-grade cervical disease. Furthermore, subjects without a persistent infection with HPV16/18 were unlikely to have HPV16/18-related high-grade cervical disease. These results suggest that persistent infection with HPV16/18 meets the criteria for a surrogate endpoint for HPV16/18-related high-grade cervical disease and may be used as such in future clinical studies with prophylactic HPV vaccines and in natural history studies.

Keywords: HPV; Prentice criteria; cervical cancer; cervical intraepithelial neoplasia; statistics; surrogate endpoint.

Figure 1.

Timeline of HPV16/18 positivity in subjects who developed HPV16/18-related CIN2+. Each horizontal line corresponds to one of the 39 cases; the horizontal axis shows time since entering the study. Circles indicate cervical swab sampling visits: open circles are shown when the subject was HPV DNA negative to the type which was later present in the disease; closed circles show DNA positivity to that HPV type. The closed triangle indicates the diagnosis of HPV16/18-related CIN2, CIN3 or AIS. Though the definition of persistent infection allowed for a swab or biopsy sample to be positive for the same HPV type after a pathology panel diagnosis of disease, in all of the cases shown in Figure 1, the persistent infection was detected prior to definitive therapy.