Epidemiology and Pathogenesis

There are an estimated 6.2 million new cases of oncogenic HPV infections occurring in the US each year, and approximately 20 million Americans are infected with HPV at any one time (CDC 2004). High-risk or oncogenic HPV infections can cause precancerous cervical lesions that are detected by routine cytological screening with the Papanicolaou (Pap) test. If these lesions are left undiagnosed they may progress to invasive cervical cancer within a few months to several years (depending on the precancerous lesion grade). Invasive cervical cancer is the second most common cancer in women worldwide. In the US, there are still more than 9,000 cases of cervical cancer and more than 3,000 deaths from the disease annually (Jemal et al. 2006).

Risk determinants for HPV infection that have been identified in various cross-sectional and prospective cohort studies include the number of sexual partners (lifetime and recent), age at first intercourse, smoking, oral contraceptive (OC) use, other sexually transmitted infections (STIs) (e.g., chlamydia and herpes simplex vi rus), chronic inflammation, immunosuppressive conditions including HIV infection, and parity (Trottier and Franco 2006). Nevertheless, in addition to sexual activity correlates, the most consistent determinant of HPV infection is age, with most studies indicating a sharp decrease in risk after the age of 30. The decrease in risk of HPV infection with increasing age seems to be independent of changes in sexual behavior, suggesting a role for immune response.

The peak in HPV prevalence among women younger than 30 years of age is followed by a decline in prevalence until age 45-50 and then a second peak in the peri- or postmenopausal years (Trottier and Franco 2006). Although the reason for this second, menopausal peak is not clear, it could be attributed to mechanisms, such as reactivation of latent infections acquired earlier in life due to a gradual loss of type-specific immunity or to acquisition of new infections due to sexual contacts with new partners later in life.

For each new case of invasive cancer found by Pap cytology, estimates suggest that there are approximately 50-100 squamous intraepithelial lesions. Women with these precancerous lesions need close monitoring by cytology and, if results persist, by colposcopy and biopsy.

Most infections seem to clear spontaneously; cohort studies have consistently found that only a small proportion of women positive for a given HPV type are found to have the same type in subsequent specimens (Richardson et al. 2003). Whether infections clear completely or the virus remains latent in basal cells at undetectable levels is a matter of debate and cannot be verified empirically. What is clear, however, is the fact that risk of subsequent cervical intraepithelial neoplasia (CIN) is proportional to the number of specimens testing positive for HPV (Ho et al. 1995). This suggests that carcinogenic development results from HPV infections that persist productively (i.e., with sustained viral replication within the squamous epithelium) for prolonged periods of time.

Mao et al. (2006) studied the natural history of high-risk HPVs in the control group of their HPV-16 L1 VLP vaccine clinical trial. They demonstrated that histologic changes become apparent shortly after HPV16 infection. In 11 of the 12 cases, CIN was identified 6-12 months after detection of HPV 16 DNA. Thus, years of persistent infection were not required before significant histologic changes such as CIN2/3 were seen. The median time to clearance of persistent infections (20.7 months) was similar to other previously published reports (Ho et al. 1995).

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