Evidence based appropriate triage strategies for implementing high risk HPV as primary technology in cervical cancer screening

Primary cervical cancer screening by HPV testing for high risk human papillomavirus (hrHPV) is expected to replace cytology-based programs in many parts of the world. Its high sensitivity and negative predictive value permit longer screening intervals up to beyond five years. However, low positive predictive value can lead to unnecessary referrals and overtreatment since most hrHPV infections are transient and will not develop disease. Therefore risk stratification is needed to effectively triage and identify women among the hrHPV positives, who are at an increased risk of cervical (pre) cancer who need further diagnostic evaluation to decide on further management. Several triage strategies like HPV16/18 genotyping, p16/Ki67 dual staining and DNA methylation markers (CADM1, MAL and miR-124-2) have been evaluated to determine suitable triage options. Triage with p16/Ki-67 dual-stain provided better long-term risk stratification than cytology with significant reduction in cumulative 5 years CIN3+ risk in p16/Ki-67 negative women. DNA methylation assays have shown higher specificity than cytology and higher sensitivity than HPV16/18 genotyping with added advantages of reproducibility and application on self-collected samples. Based on current evidence, Pap cytology with or without additional HPV16/18 genotyping remains the most recommended triage strategies for primary HPV screening. Other strategies will need more longitudinal studies to provide evidence of risk reduction in test negative results. WHO recommends Visual Inspection with Acetic Acid (VIA) for triaging HPV-positive women in LMIC settings. An optimal triage strategy that can be integrated with primary HPV screening should be able to segregate and reassure the large majority of women who are at very low risk of cervical cancer.