The role of human papillomavirus testing in the management of women with low‐grade abnormalities: multicentre randomised controlled trial

Abstract

Objective To assess the value of a single human papillomavirus (HPV) test in making decisions on management of women with cervical cytology showing borderline nuclear abnormality (BNA) or mild dyskaryosis. In particular, to determine whether information on high-risk (hr) HPV status would be valuable in the choice between (1) cytological surveillance versus immediate referral to colposcopy, and (2) at colposcopy, between biopsy and recall versus immediate large loop excision of the transformation zone (LLETZ).Design Multicentre individually randomised controlled trial, nested within the NHS Cervical Screening Programmes, investigating the value of HPV testing by testing for interactions between HPV status and (1) cytological surveillance versus colposcopy, and (2) biopsy and recall versus immediate LLETZ.Setting Grampian, Tayside and Nottingham.Population Women (n = 4439), aged 20-59 years, with a cytology test showing borderline nuclear abnormalities or mild dyskaryosis during October 1999 to October 2002.Methods High-risk HPV status was determined at recruitment using the polymerase chain reaction assay with the GP5+/6+ general primer system. The results of this HPV testing were not disclosed to either the participating women or to those involved in their management. Women were randomised to either (1) 6-monthly cytological screening in primary care or (2) referral for colposcopy. Human papillomavirus status was used to stratify both randomisations. All women were followed for 3 years, concluding with an invitation to an exit appointment at which colposcopic examination was undertaken. In addition, in women who were randomised to initial colposcopy and underwent colposcopy, the association between hrHPV status and presence of cervical intraepithelial neoplasia (CIN) grade 2 or more severe disease (henceforth CIN2 or worse) was examined.Main outcome measures Sensitivity, specificity, positive and negative predictive values of the HPV test for predicting CIN2 or worse and the implications for the choice of management between cytological surveillance and immediate referral for colposcopy.Results There were no significant interactions between management and HPV status. Hence, in women with mild dyskaryosis or BNA who are HPV positive, there is no advantage of (1) immediate colposcopy over cytological surveillance (P = 0.76) or (2) immediate LLETZ over biopsy and recall (P = 0.27). The sensitivity of HPV testing for detection of CIN2 or worse was 75.2% (95% CI 68.8-81.0%) among women with mild dyskaryosis and 69.9% (95% CI 61.7-77.3%) among those with BNA. Specificity was higher in those with BNA (71.3%; 95% CI 68.5-74.1%) than in those with mild dyskaryosis (46.9%; 95% CI 42.2-51.6%). Sensitivity decreased with increasing age whereas specificity increased. The negative predictive value was high, particularly among women with BNA (94.5%; 95% CI 92.9-96.0%). Across all ages, 22% of women who had CIN2 or worse were HPV negative. Conversely, 40% of those who were HPV positive did not have CIN. HPV was a much more relia...

Human papillomavirus‐based triage of women showing a cervical cytology result of borderline or mild dyskaryosis

“…4 At randomisation, an endocervical sample was taken to identify the presence of DNA of 14 high-risk human papillomavirus types (hrHPV) using a polymerase chain reaction (PCR) with GP5+/6+ primers and enzyme immunoassay identification. The results of HPV testing did not interfere with management.…”

Reconsidering Primary HPV Testing in Cervical Cancer Screening

“…Giving the fact that HPV testing has been shown to have similar sensitivity but more overdiagnosis than the Pap test [25][26][27][28], and also giving the fact that false negative results may be higher than previously suspected [25,26,32], primary screening with HPV testing in European countries as well as in the U.S. should be reconsidered. Resources saved in molecular testing may well be addressed in implementing vaccination strategies that are still underused and possibly must include males as well as women [44,45].…”

“…This false negative rate is similar to that observed by Cotton and coll. who showed that 22% of women who had CIN 2 or worse were HPV negative at baseline (TOMBOLA trial) [26]. It is difficult to accept these figures when one talks of extending rescreening intervals such as those proposed by HPV testing algorithms.…”

Cervical Cancer Screening Strategies: Not the Test You Take, but the Decision You Make

“…At the same conclusions arrived Cotton and coll. showing a false negative rate of 22% in women with a high grade lesions or worse who tested HPV negative at baseline (TOMBOLA trial) [14]. Nevertheless, a study designed to evaluate the efficacy of HPV-based strategies in four European randomised controlled trials showed that HPV testing was supposed to provide 60-70% greater protection against cervical cancer compared with cytology [15].…”