Negative human papillomavirus testing in normal smears selects a population at low risk for developing high-grade cervical lesions

Abstract

High-risk human papillomaviruses (HR-HPV) are the necessary cause of cervical carcinomas and there is an increasing interest in using HR-HPV DNA detection in adjunction to cytological examination for primary cervical screening. To determine whether women with a normal smear negative for HR-HPV DNA detection with the Hybrid Capture II assay might represent a low-risk population for developing a high-grade squamous intraepithelial lesion (HSIL), 4401 women have been followed in a period of 12 -72 months (median ¼ 34 months). During this follow-up, four HSIL and one microinvasive carcinoma have been detected in this cohort (three in the cohort of 3526 women 429 years). The global negative predictive value (NPV) of double-negative tests is thus of 99.9% (ninetyfive percent confidence interval (95% CI): 99.8 -100%), whereas cytology alone gives an NPV of 99.2% (95% CI: 98.9 -99.5%). If we obtain a second negative HR-HPV test 1 -2 years after the initial test, the NPV is 100%. The NPV is also of 100% in the cohort of women 449 years. We conclude that all these women could be safely screened at longer intervals between 3 and 5 years. This policy will offset the increased costs induced by an additional HR-HPV testing in primary screening. 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(Cuzick et al, , 1999(Cuzick et al, , 2003Meijer et al, 1998;Clavel et al, 1999Clavel et al, , 2001Kuhn 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, ...

Long-term protective effect of high-risk human papillomavirus testing in population-based cervical screening

“…The overall detection rate by cytology of 0.3% lesions XCIN3 at baseline and 0.5% after 5 years in this study is comparable to the detection rate of lesions XCIN3 in cervical cancer screening in The Netherlands (Bos et al, 2002;Anttila et al, 2004). The high NPV of the combination of a negative hrHPV test and a normal smear is in accordance with Clavel et al (2004), who reported an NPV of 99.9% in a partly hospital-based population, with a much shorter interval (median 2.8 years) for women of 15 -79 years of age. Sherman reported an NPV of 99.2% for hrHPV in cervical lavage specimens during annual screening for women of 16 -94 years of age (Sherman et al, 2003).…”

Human papillomavirus testing in cervical cancer screening

“…In their 5-year cohort study in The Netherlands of 2810 women aged 30 -60 years with normal cytology, Bulkmans et al (2005) show that, in agreement with previous findings from the US (Sherman et al, 2003), France (Clavel et al, 2004) and the UK (Cuzick et al, 2003;Peto et al, 2004), HR HPV testing combined with cytology has higher sensitivity and higher negative predictive value for cervical intraepithelial neoplasia (CIN) 3 and cancer than cytology alone. Specificity was, however, slightly lower for HPV testing and cytology (93%) than cytology alone (95%).…”

Cumulative 5‐year diagnoses of CIN2, CIN3 or cervical cancer after concurrent high‐risk HPV and cytology testing in a primary screening setting

“…Five cases (4 HSIL and 1 micro-invasive carcinoma) were found in 4,401 women (0.1%) after 34 months by Clavel et al 16 Sherman et al 14 reported that during the first 45 months the cumulative incidence of CIN3 was 0.16% in HPV and cytology double negatives. It is not surprising that no CIN2þ was detected by colposcopy/biopsy in random samples of about 200 to 250 women.…”