Adjunctive Testing by Cytology, p16/Ki-67 Dual-Stained Cytology or HPV16/18 E6 Oncoprotein for the Management of HPV16/18 Screen-Positive Women.

HPV16/18 genotyping is unable to accurately discriminate non-progressive infections from those that will progress to cervical cancer. Our study aimed to assesses if additional testing either with liquid-based cytology (LBC) or the putative progression markers p16/Ki-67 and HPV16/18 E6 oncoprotein (E6) can improve the efficiency of HPV16/18 genotyping for triaging hrHPV positive women through better cancer risk stratification.Women attending colposcopy after positive HPV16/18 genotyping results within the FRIDA hrHPV-based screening study in Tlaxcala, Mexico, underwent further testing with LBC, p16/Ki-67 dual-stained cytology (DS) and E6. We calculated measures of test performance for detecting histologically-confirmed cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and grade 3 or higher (CIN3+). 475 (64.3%) of 739 HPV16/18 positive women had complete results for all tests. Triage positivity rates were 14.1%, 18.5% and 24.4%, for LBC, E6 and DS, respectively. Compared to LBC, DS had higher sensitivity (24.4% vs 60.0%) although lower specificity (87.0% vs 79.3%) for CIN3+ (p<0.001), whereas E6 had a sensitivity of 37.8% and a specificity of 83.5%. No invasive cancer was missed by DS or E6, but 75% were in normal cytology. DS test was associated with nearly 75% reduction of colposcopy referrals compared to the direct referral of all HPV16/18 positive women, giving the least number of colposcopies (n=4.3) per CIN3+ detected. We show that adjunctive testing of HPV16/18 positive women with DS may greatly reduce unnecessary colposcopy referrals within HPV-based screening employing HPV16/18 genotyping while retaining acceptable sensitivity for CIN2+ and CIN3+.