Background: In addition to oncogenic Human papillomaviruses (HPV), several cofactors are needed in cervical carcinogenesis, but it is poorly understood whether these HPV cofactors associated with incident i) CIN1 are different from those required for progression to ii) CIN2 and iii) to CIN3.

Objectives: To gain further insight in the true biological differences between CIN1, CIN2 and CIN3, we assessed HPV cofactors increasing the risk of incident CIN1, CIN2 and CIN3, for the first time in a longitudinal setting.

Methods: Data of the NIS Cohort (n=3,187) and the LAMS Study (n=12,114) were combined, and cofactors associated with progression to CIN1, CIN2 and CIN3 were analysed using multinomial logistic regression models with all covariates recorded at baseline HR-HPV-positive women (n=1,105), who represent a sub-cohort of all 1,865 women prospectively followed-up in both studies.

Results: Altogether, 90 (4.8%), 39 (2.1%) and 14 (1.4%) cases progressed to CIN1, CIN2 and CIN3, respectively. Baseline HR-HPV was the single most powerful predictor of incident CIN1, CIN2 and CIN3. When controlled for residual HPV confounding by analyzing HR-HPV positive women only, the risk profiles of incident CIN1, CIN2 and CIN3 were unique, i.e., completely different HPV cofactors were associated with progression to CIN1, CIN2 and CIN3 in univariate and multivariate analysis, irrespective of whether non-progression incident CIN1 or CIN2 was used as the reference outcome.

Conclusions: HPV cofactors associated with progression to CIN1, CIN2 and CIN3 display unique profiles, implicating genuine biological differences between the three CIN grades, which revisits the concept of combining CIN2 with CIN3 or (as also suggested) with CIN1.