Incidence and Burden. Human papillomaviruses (HPVs) are extremely common and widespread. Genital HPV infection is a sexually transmitted disease with an incidence of 5 percent to 40 percent among sexually active women. HPVs are etiologically linked to genital cancers, especially cervical cancer, and infection with a high-risk HPV is by far the most significant risk factor for developing cervical cancer—more than 90 percent of cervical cancers contain HPV DNA. Cervical cancer is approximately the number-six cancer among women in developed countries but its the number-one killer from cancer in developing countries, where Pap smears are not readily available. On a worldwide basis, cervical cancer is the number-two cause of death from cancer in women, after cancer of the breast. It has been estimated that HPV infection is involved in approximately 15 percent of all human cancers.
Pathobiology. HPVs are small, nonenveloped DNA viruses that replicate in the nucleus of the host cell, leading to lesions, warts, and tumors. They are epitheliotropic: replication occurs only in epithelial cells, primarily in the differentiated layers of the epidermis. More than 70 different HPV genotypes have been identified and classified into three large groups according to the region of epithelia they tend to infect:
Cutaneous nongenital HPVs are commonly seen in dermatological practices and do not appear to have malignant potential. Several million cases are present in the United States at any given time. It is not clear that there would be demand for a prophylactic vaccine, although a therapeutic vaccine might well be important.
Epidermodysplasia verruciformis-specific HPVs include almost one-half of all known HPV types and are found principally in patients with a predisposition to develop widespread, chronic, nongenital lesions. Some of these patients go on to develop malignancies, but this is a very rare condition.
Mucosal HPVs include almost 20 different types identified to date. Some are low-risk types associated with nonmalignant disease, particularly HPV-6 and 11. Others are high-risk types that seem to have malignant potential, particularly HPV-16, 18, 31, and 45. In a study of viral DNA in 1,000 cervical cancers from around the world, HPV-16 is by far the most common type, although HPV-18 is also common in Southeast Asia. However, the DNA of multiple HPV types is found in both benign and malignant genital lesions, for which reason a vaccine against genital HPV will need to be polyvalent.
About 50 percent of cervical infections are with high-risk HPVs, but the majority are clinically inapparent and self-limited. Only about 10 percent of the infected women have cytopathological changes on Pap smears, and most of