The Role of Human Papillomavirus Testing in the Management of Women With Low-Grade Abnormalities: Multicentre Randomized Controlled Trial

Abstract

Cytology testing in the NHS Cervical Screening Programs in the United Kingdom has identified over a quarter of a million women with precancerous low-grade abnormalities (mild dyskaryosis or borderline nuclear abnormalities [BNA]). Some investigators have suggested that human papillomavirus (HPV) testing could help decide which of these women should be referred for colposcopy and which could safely be returned to routine recall. This multicenter randomized-controlled trial used data from a previous Trial Of Management of Borderline and Other Low-grade Abnormal smears Group (TOMBOLA) trial to determine whether an HPV test is useful among women with mild dyskaryosis or BNA in the choice between cytological surveillance and colposcopy, and after referral whether HPV testing is useful in choosing treatment (either immediate large loop excision of the transformation zone (LLETZ) or biopsy with selective recall. The study subjects were 4439 women, 20 to 59 years of age, with mild dyskaryosis or BNA at enrollment. HPV analysis was performed using the polymerase chain reaction assay with the GP5+/6+ general primer system. Both the study subjects and those involved in management were blinded to the HPV testing results. In the first of 2 randomizations, women were assigned to either cytological surveillance every 6 months or referral for immediate colposcopy. In the second randomization, women referred for colposcopy were assigned either to immediate LLETZ or biopsies with selective recall for LLETZ. Both randomizations were stratified for HPV status and age. In addition, the association between HPV status and the presence of cervical intraepithelial neoplasia (CIN) grade 2 or more severe disease (CIN2 or worse) was examined in women who underwent colposcopy. At the end of the 3-year follow-up, all women were invited for an exit examination, which included colposcopy. No significant interactions were found between management and HPV status, showing that HPV positivity among women with low-grade cytologic abnormalities at recruitment was not effective in the choice of immediate colposcopy over cytological surveillance (P = 0.76) or immediate LLETZ over biopsy and recall (P = 0.27). No difference was found between women with mild dyskaryosis and BNA in the sensitivity of a single HPV test in detection of CIN2 or worse, whereas specificity was higher in those with BNA (71.3%; 95% confidence interval [CI], 68.5%–74.1% vs. 46.9%; 95% CI, 42.2%–51.6%). With increasing age, the sensitivity decreased and the specificity increased. There was a high negative predictive value, especially among women with BNA (94.5%; 95% CI, 92.9%–96.0%). About 22% of women across all ages with CIN2 or worse were HPV negative. Conversely, 40% of HPV positive women did not have CIN. HPV was a more reliable predictor among women aged 40 or more compared with younger women. These findings indicate that a single HPV test may be useful in women over 40 years of age in determining which women with low-grade abnormal cytology should be referred for colposcopy, but may not be useful in women 40 years of age or less, or for determining the most effective management at colposcopy.