Cofactors in Human Papillomavirus Carcinogenesis
Human papillomavirus (HPV) infection is the necessary cause of cervical cancer (CC) and other HPV-related malignancies, yet by itself is not sufficient for malignant progression. A myriad of co-factors influences the risk that an HPV infection persists and progress to precancerous lesions and invasive disease. Understanding these cofactors is crucial for risk stratification and informing comprehensive preventive strategies-complementing HPV vaccination and screening-to further reduce the incidence of cervical and other HPV-associated cancers.This chapter reviews the epidemiological and mechanistic evidence for key cofactors in HPV-driven carcinogenesis. The most established cofactors-including tobacco smoking, immunosuppression (particularly HIV infection), long-term use of oral contraceptives, high parity, and coinfection with other sexually transmitted infections-have consistently been associated with increased risk of HPV persistence and disease progression. We discuss their prevalence, magnitude of risk, and biological plausibility. Emerging and less established cofactors, such as the cervical microbiome, nutritional status and diet, and host genetic polymorphisms, which may modulate immune responses to HPV or the propensity for viral persistence are also explored.