Usually, HPV infections do not persist. Those that do persist may remain latent for many years. Most women who are exposed have no clinical evidence of disease, and the infection is eventually suppressed or eliminated (17). Other women exhibit low-grade cervical lesions that mostly regress spontaneously. In the vast majority of cases, the infection will clear in 9 to 15 months (23). A small minority of women exposed to HPV develops persistent infection that may progress to CIN (17,24). Persistent high-risk HPV infection increases the risk of high-grade disease 300fold and is required for the development and maintenance of CIN 3 (25,26). Factors that may have a role in persistence and progression include smoking, contraceptive use, infection with other sexually transmitted diseases, or nutrition (17,22). Any factor that inﬂuences the integration of HPV DNA into the human genome may cause progression to invasive disease (27).
Because HPV infection is a necessary factor in the development of cervical neoplasia, an important step in primary prevention was the development of a prophylactic vaccine to protect against HPV infection. The development of prophylactic vaccination became possible through the development of protein mimics that simulate the outermost protein capsid of the virus and are termed viruslike particles (VLPs) (28). Gardasil (Merck, NJ, USA), a quadrivalent vaccine containing the VLPs for HPV-6, -11, -16, and -18, was approved by the U.S. Food and Drug Administration (FDA) in 2006; and Cervarix (GlaxoSmithKline, Middlesex, U.K.), a bivalent vaccine, was approved in 2009, and contains the VLPs to types 16 and 18. Clinical trials demonstrated that both the bivalent and quadrivalent vaccines are highly efficient in preventing CIN 2, CIN 3, or adenocarcinoma in situ caused by HPV-16 and -18 in women from 15 to 26 years of age (29,30). For the population who are seronegative and HPV DNA negative for HPV-16 and -18 at vaccination and received all three vaccinations, the efficacy is 100% (31,32). This protection is documented to last as long as 6.4 years after vaccination (31).
In a small subset of women who were seropositive for HPV-16 or -18, but DNA negative, the vaccine efficacy remained at 100% (29,30). This suggests that past exposure and clearance of the virus does not reduce the efficacy of the vaccine. On the other hand, the vaccines do not show efficacy in women who are HPV-16 and -18 DNA positive at the time of entry onto the study. This indicates that the vaccines are not able clear an active infection and cannot be used to treat CIN.
Since HPV-16 and -18 are contained in 52% of CIN and 70% of invasive cancers, the data concerning cross-protection from the other high-risk types are important (33). The bivalent vaccine demonstrates protection from persistent infection with HPV types 31, 33, and 45 and protection from CIN-related HPV-31 (29). Quadrivalent vaccine data showing cross-protection against CIN 2 or greater and against HPV 31 exist, but this indication is not included in the FDA-approved labeling (34).
The 3-year follow-up studies of both vaccine products exhibit a reduction in referrals to colposcopy by 26% and 20%, respectively (29,35). This is accompanied by a reduction in excisional procedures of 69% and 42% for the bivalent and quadrivalent products, respectively (29,35). The additional reduction may come from cross-protection against nonvaccine specific HPV types.