Chapter 2: Natural history of anogenital human papillomavirus infection and neoplasia.

This chapter suggests promising areas of future epidemiologic research on human papillomavirus (HPV) and anogenital cancer, organized around our understanding of cervical carcinogenesis. The major steps in cervical carcinogenesis include HPV infection, HPV persistence over a certain period of time, progression to precancer, and invasion. Backward steps include clearance of HPV infection and regression of precancer. Additional studies of incident HPV infections among virgins initiating sexual activity could clarify the earliest aspects of transmission and immune response. Research on older women and their male partners should focus on understanding the determinants of varying age-specific HPV prevalence curves and underlying dynamics of viral persistence, clearance, and latency. It will be particularly important for epidemiologists to define HPV persistence rigorously in order to guide clinical management and vaccine trials. Intensive longitudinal studies that collect visual, microscopic (cytologic and histologic), and molecular data will be needed to understand the fate of individual HPV infections and to clarify whether multiple, concurrent infections act independently on the cervix. Case-control designs will be useful mainly in searching for new biomarkers of risk of progression among HPV-infected women that could then be validated prospectively. Prospective confirmation is also needed for the etiologic cofactors established by case-control studies of invasive cervical cancer. Much of the knowledge about cervical cancer might apply to anal neoplasia. Epidemiologic studies of other genital tumors such as penile neoplasia are still needed, but multicentric groups must place great emphasis on measurement technology, given the difficulty in obtaining reliable comprehensive measurements.