It is now well established that oncogenic (high-risk) human papillomaviruses (HPV) are a necessary causal factor in the development of cervical intraepithelial and invasive neoplasias (Lorincz et al, 1992; Bosch et al, 1995; Walboomers et al, 1999; Zur Hausen, 2002). Infections with high-risk HPV (HR-HPV) are associated with a relative risk of between 8 and 11 for the development of squamous intraepithelial lesions (SIL) (Gaarenstroom et al, 1994). Moreover, only low-grade SIL (LSIL) containing HR-HPV progress to high-grade SIL (HSIL) (Koutsky et al, 1992). Owing to this, there is an increasing interest in using HPV DNA detection either alone or in addition to classic cytological examination for primary cervical screening (Cuzick et al, 1995, 1999, 2003; Meijer et al, 1998; Clavel et al, 1999, 2001; Kuhn et al, 2000; Ratnam et al, 2000; Schiffman et al, 2000; Schneider et al 2000; Kjaer et al, 2002; Petry et al, 2003; Lorincz and Richart, 2003; Sherman et al, 2003). Most authors consider that a positive HPV testing selects a population at high risk for developing an HSIL, while a negative HPV testing has a very good negative predictive value (NPV). Indeed, considering that the mean time from detectable LSIL to preclinical invasive cancer is 12–13 years (Gustafson and Adami, 1989), Meijer et al (1998) have proposed that women with cytologically normal smears and a negative HR-HPV test could be rescreened every 8 years.
Hybrid Capture-II (HC-II), a commercial HPV detection test, (Digene, Gaithersburg, MD, USA) was introduced 7 years ago (Lorincz, 1996). Hybrid Capture-II is a nonradioactive, reproducible, relatively rapid, liquid hybridisation assay in microtiters designed to detect 18 HPV types divided into high-risk (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) and low-risk (types 6, 11, 42, 43 and 44) groups. The sensitivity of this assay is quite similar to that of polymerase chain reaction (PCR) (Peyton et al, 1998). Recently, the Food and Drug Administration in the USA has authorised the use of this assay in women aged 30 years and older for primary screening in adjunction to cytology. In a recent preliminary study, using this test in women with normal smears, we have shown that recurrent infection detected with HC-II was associated with a relative risk of incident HSIL of 237.3 when HR-HPV test remained positive at two controls. In contrast, in the cohort of 2432 women testing negative for HR-HPV infection followed on a period of 60 months, only two women developed an HSIL (Bory et al, 2002). Thus the NPV of a negative test with HC-II could be useful in primary screening when associated with a smear within normal limits.
At the present time, there are few longitudinal studies with a detailed and prolonged follow-up of women with a normal smear with a negative HR-HPV testing (Kjaer et al, 2002; Sherman et al, 2003). Thus, the aim of the present study is to evaluate on a large population of women with an initial smear within normal limits the usefulness and limitations of a negative HR-HPV testing in such women. For that, we have followed on a period from 12 to 72 months 4401 women with a normal smear and a negative HR-HPV testing at enrolment. The end point in all these women was the detection of an HSIL at the histological examination.