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

Abstract

We prospectively evaluated the 5-year predictive values of adding high-risk human papillomavirus (hrHPV) testing to cytology for the detection of Xcervical intraepithelial neoplasia (CIN)3 lesions in a population-based cohort of 2810 women. At baseline, nine (0.3%) women had prevalent lesions XCIN3, all being hrHPV positive. After 5 years of follow-up, four (6.5%) of the 62 hrHPV-positive women with normal cytology developed lesions XCIN3, vs only one (0.05%) of the 2175 hrHPV-negative women with normal cytology. High-risk human papillomavirus testing or combined screening revealed a much higher sensitivity, at the cost of a small decrease in specificity, and a higher negative predictive value for the detection of lesions XCIN3 till the next screening round (5 years) than cytology alone. Cervical screening by cytology is known to yield a substantial proportion of both false-positive and false-negative smears. Since infection with high-risk human papillomavirus (hrHPV) is considered to be the cause of cervical carcinoma, it has been suggested that adding hrHPV testing to cervical screening might improve screening in terms of reducing false-positive and falsenegative smears (Rozendaal et al, 2000; Cuzick et al, 2003). However, long-term data are needed before hrHPV testing can be implemented in population-based cervical screening. Here, we present for the first time the prospective long-term (5 years) predictive values of routine hrHPV testing in population-based cervical screening in The Netherlands. MATERIAL AND METHODSA cohort of 3170 women (mean age 45 years; range 29 -61 years) was enrolled from March 1995 till October 1998 by 60 general practitioners in the small district of Amstelveen, The Netherlands. In all, 194 women were excluded because of abnormal cervical cytology and/or histology during 2 years preceding the intake, 159 women because of a negative b-globin PCR test, and seven women because of inadequate cytology, leaving 2810 women for analysis. Cytological screening was performed according to the CISOE-A classification, routinely used in cervical screening in The Netherlands, and the referral policy was according to the nationwide guidelines (Bulk et al, 2004). High-risk human papillomavirus testing was performed by GP5 þ /6 þ PCR-EIA, using a cocktail probe of 14 hrHPV types, and independent of cytology results. The hrHPV test result was blinded. Informed consent was obtained and the study was approved by the Medical Ethics Committee of the VU University Medical Center. The primary end point of the study was the detection of histologically proven cervical intraepithelial neoplasia grade 3 or cervical carcinoma (XCIN3) up to and including the next screening round (after 5 years). Follow-up data were retrieved from the Dutch nationwide pathology registry (PALGA) in 2004.Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of cytology, cytology and hrHPV testing combined, and hrHPV testing, for the detection of prevalent and incident lesions XCIN3 were compute...

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%).…”

“…The improvement in sensitivity and negative predictive value made possible by the addition of HR HPV testing to cytology supports the use of viral testing in order to increase the screening interval, although the findings of Bulkmans et al (2005) should be interpreted with some caution as their study was relatively small, and, as the authors emphasise, an increased sensitivity is implicit in performing any additional test (Franco and Ferenczy, 1999).…”

“…Follow-up studies of women with negative cytology, according to HPV status, are therefore important. In this issue, Bulkmans et al (2005) and Grainge et al (2005), using two different study designs, provide further evidence of the value of adding HPV testing to cervical cytology in screening programmes.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%).…”

“…Follow-up studies of women with negative cytology, according to HPV status, are therefore important. In this issue, Bulkmans et al (2005) and Grainge et al (2005), using two different study designs, provide further evidence of the value of adding HPV testing to cervical cytology in screening programmes.…”

Management of high-risk HPV-positive women for detection of cervical (pre)cancer

“…Large longitudinal studies have shown that screening can be improved by the introduction of a hrHPV test as a primary screening tool [14][15][16][17][18][19][20][21][22][23][24][25][26]. Compared to primary screening with Pap cytology, a primary hrHPV test has a superior sensitivity for cervical cancer [24] and its high-grade precursor lesions (cervical intraepithelial neoplasia grade 3, CIN3) [14][15][16][17][18][19][20][21]26].…”