Cervical cancer screening by Human Papillomavirus (HPV) DNA testing with cytology triage is more effective than cytology based screening. Compared to cytology, the HPV DNA test shows higher sensitivity, which allows better protection and longer screening intervals, although a lower specificity which makes it necessary to triage the women resulted positive. We have been conducting a large randomized clinical trial (New Technologies for Cervical Cancer 2 [NTCC2], NCT01837693)(1) within organized population-based screening programs in 5 Italian regions using HPV DNA as the primary test, with the aim of evaluating the HPV E6-E7 mRNA test (Aptima HPV assay, Hologic) and the p16/ki67 double staining (CINtec plus test, Roche) as the triage test in comparison to cytology.
Women were tested with HPV DNA assay (Cobas 4800 HPV assay, Roche, or Hybrid Capture 2 (HC2), Qiagen). Those positive were triaged with cytology and tested for mRNA and p16/ki67 double staining. Women with positive or inadequate cytology were referred to colposcopy, while those with negative cytology were randomised to immediate colposcopy or to 1-year HPV re-testing. Women will be followed up for at least 5 years, until the next screening round. Here the baseline results of mRNA positivity according to age, cytology, HPV type, and HPV viral load, are presented.
More than 42,000 25-64yo women have been recruited from April 2014 to April 2017. Here are included data from 35,877 samples collected up to June 2016; 2,651 (7.4%) were HPV DNA positive. Up to now, 2,453 samples have been tested also by Aptima, and 1,649 (67.2%, 95% CI 65.4-69.2) gave a positive result. Positivity was similar in all age groups, and it was higher in women with positive cytology (82.7%, 95%CI 79.0-86.0; 93.5%, 95%CI 88.3-96.8, for low and high grade, respectively) than in those with negative cytology (60.8%, 95%CI 58.5–63.1) and in women HPV16 infected (81.8%, 95%CI 76.4-86.4) compared to those infected by other high risk types (72.6%, 95%CI 69.8-75.3). Finally, positivity increased with HPVDNA viral load from 10.6% (95%CI 6.9–15.3) for women with HC2 relative light unit ratio (RLU) between 1 and 1.99, to 85.0% (95%CI 82.2–87.6) for women with HC2 RLU >10.
If used as a triage test, the mRNA test, due to the observed positivity rate, would determine a 5% immediate colposcopy referral, compared to 2% with cytology triage. Thus, the number of women referred to colposcopy would increase if the 1-year referral for HPV DNA-positive/mRNA-negative cases is maintained. Only longer interval for these women might make triage by this test more efficient than by cytology, as long as the mRNA test shows very high sensitivity.
Giorgi Rossi P, Bisanzi S, Allia E, Mongia A, Carozzi F, Gillio-Tos A, De Marco L, Ronco G, Gustinucci D, Del Mistro A, Frayle H, Iossa A, Fantacci G, Pompei G, Cesarini E, Bulletti S, Passamonti B, Rizzi M, Penon MG, Barca A, Benevolo M, and the NTCC2 Working Group. Determinants of viral oncogenes E6-E7 mRNA over-expression in a population-based large sample of women infected by high risk HPV types. J Clin Microbiol. 2017 Apr;55(4):1056-1065.