The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].).

In contrast to cervical cancer, integration of human papillomavirus (HPV) DNA into the host genome has been considered a rare event in cancer precursor lesions (cervical intraepithelial neoplasia [CIN]). With our new real-time PCR method, we demonstrated that integrated HPV type 16 (HPV16) is already present in CIN lesions. The physical state of HPV16 and the viral load were simultaneously detected. A unique region of the E2 open reading frame (ORF) that is most often deleted during HPV16 integration is targeted by one set of PCR primers and a probe, and another set targets the E6 ORF. In episomal form, both targets should be equivalent, while in integrated form, the copy numbers of E2 would be less than those of E6. The method was tested with DNAs from 31 cervical lesions (non-CIN to CINIII) from 24 women prospectively followed up for 10 years. This report presents viral load and integration results from the largest series of CIN lesions described to date. Only one sample contained exclusively episomal HPV16 DNA, and this lesion regressed spontaneously. Samples from another patient, with only integrated HPV16, rapidly progressed from CINI to CINIII in 2 years. In all other patients, episomal and integrated forms of HPV16 DNA were found to coexist. Rapid progression of the CIN lesions was closely associated with a heavy load of integrated HPV16. Thus, the method described here is a very sensitive tool with which to assess the physical state of HPV, which is useful in predicting disease progression.Human papillomaviruses (HPVs) comprise more than 120 putative virus types, of which 85 types have been fully sequenced, and approximately 40 types are associated with lesions of the anogenital tract. Infection with high-risk (oncogenic) types of HPV (HPV16 [HPV type 16],) is a well-established risk factor for the development of cervical carcinoma (34, 42), which is the second most common female malignancy worldwide. The most common oncogenic HPV type in cervical cancer is HPV16, which is detectable in more than 50% of the cases (2). Premalignant cervical lesions are commonly staged according to increasing severity, as cervical intraepithelial neoplasia I (CINI), CINII, and CINIII, where CINIII represents severe dysplasia or cancer in situ. NCIN here denotes HPV-infected lesions without signs of neoplasia. Previous studies suggested that benign HPV lesions and low-grade intraepithelial lesions (CINI) mostly contain the viral sequences only as episomes (4,13,15,30,32,41). In contrast, viral DNA is integrated into the host genome in virtually all cases of cervical carcinomas and their derivate cell lines (3, 6-9, 14, 22, 36). No previous studies are available in which the physical state and viral load of HPV in premalignant cervical lesions (CIN) have been assessed with new sensitive and quantitative methods such as real-time PCR.Viral DNA integration into host cell DNA usually disrupts the E1 and E2 open reading frames (ORFs). In contrast, the E6 and E7 ORFs and LCR (long control region) generally remain intact (7,22,28,...

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Primary HPV DNA-based screening with cytology triage and repeat HPV DNA testing of cytology-negative women appears to be the most feasible cervical screening strategy.

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