Mechanisms and predictors of high-risk human papillomavirus (HPV) clearance in the uterine cervix

Abstract

Cervical cancer (CC) and its precursor lesions (CIN) are unique in that we can study the natural history of one disease at two different levels; i) by assessing the clinical lesions, and ii) by analysing the viral events of human papillomavirus (HPV) infections, their prime etiological agent. In this review, we are interested in mechanisms and predictors of clearance of oncogenic HPV infections in the uterine cervix. The outcome (natural history) of CIN has been well established by a large number of prospective cohort studies covering over 25,000 patients, and the figures for regression, persistence and progression are well established. The outcome of HPV infections is far more complex with at least six distinct patterns being demonstrated in long-term cohort studies. There is little doubt that the mechanistic explanation for HPV clearance is by specific immunological reactions, where competent humoral and cell-mediated immune mediators are needed. To understand this process in detail still necessitates a substantial amount of clinical and laboratory research, however. In general, HPV outcomes follow the pattern where a dynamic balance exists between incident infections and virus clearance. Following a rapid accumulation of incident infections after onset of sexual activity (women < 20 years of age), there is a transition of this balance in favour of virus clearance soon after age 25. This explains the constantly declining age-specific prevalence of HPV infections until menopause. Failure to eradicate the virus at postmenopause is not uncommon, however, explaining the deep second peak in HPV prevalence now reported in many different populations. The importance of HPV clearance/non clearance (= persistence) has been recognised recently, and the number of studies addressing these issues has increased substantially during the past few years. The data are now rather unanimous concerning the times and rates (usually expressed per 1,000 women/months at risk, WMR) of HPV clearance. On the other hand, data are still incomplete and in part inconsistent as to the cofactors that regulate these events. A wide variety of variables have been explored as potential co-determinants and/or predictors of HPV clearance, as reviewed in this communication. Until now, all efforts attempting to identify suitable biomarkers as such predictors, have been disappointing, but fortunately, this is a largely unexplored area as yet. Similarly, data on the two extremes of life, i.e., early infancy and postmenopause, are still far too fragmentary to enable creating a comprehensive view, how these viral infections behave in early life, and what makes many women incapable of clearing their virus at postmenopause. Both issues are of utmost importance and have widespread clinical implications; we need to know how and why some infants and children contract HR-HPV infections well before the onset of their sexual activity, to be able to select the proper targets for prophylactic HPV vaccination. Similarly, we need to know why some women over 55 years of age are likely to remain HR-HPV carriers, while the vast majority successfully clears their infection well before the menopausal age. Early detection of cervical cancer precursors among these elderly HR-HPV positive women past the usual age of organised screening remains a major challenge also in the future.