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ARTICLES Epidemiologic Evidence Showing That Human Papillomavirus Infection Causes Most Cervical Intraepithelial Neoplasia Mark H.

Schiffman, Heidi M. Bauer, Robert N. Hoover, Andrew G. Glass, Diane M. Cadell, Brenda B. Rush, David R. Scott, Mark E. Sherman, Robert J. Kurman, Sholom Wacholder, Cynthia K. Stanton, M. Michele Manos* Background: Experimental studies have provided strong evidence that human papillomavirus (HPV) is the long- sought venereal cause of cervical neoplasia, but the epidemiologic evidence has been inconsistent. Purpose: Given improvements in HPV testing that have revealed a strong link between sexual activity history and cervical HPV infection, we conducted a large case-control study of HPV and cervical intraepithelial neoplasia (CIN) to evaluate whether sexual behavior and the other estab- lished risk factors for CIN influence risk primarily via HPV infection. Methods: We studied

500 women with CIN and

500 control subjects receiving cytologic screen- ing at Kaiser Permanente, a large prepaid health plan, in Portland, Ore. The established epidemiologic risk factors for CIN were assessed by telephone interview. We performed HPV testing of cervicovaginal lavage speci- mens by gene amplification using polymerase chain reaction with a consensus primer to target the LI gene region of HPV. Unconditional logistic regression analysis was used to estimate relative risk of CIN and to adjust the epidemiologic associations for HPV test results to demonstrate whether the associations were mediated by HPV. Results: The case subjects demonstrated the typical epidemiologic profile of CIN: They had more sex part- ners, more cigarette smoking, earlier ages at first sexual intercourse, and lower socioeconomic status. Statistical adjustment for HPV infection substantially reduced the size of each of these case-control differences. Seventy-six percent of cases could be attributed to HPV infection;

the results of cytologic review suggested that the true percentage was even higher. Once HPV infection was taken into account, an association of parity with risk of CIN was observed in both HPV-negative and HPV- positive women. Conclusion: The data show that the great majority of all grades of CIN can be attributed to HPV infection, particularly with the cancer-associated types of HPV. Implications: In light of this conclusion, the investigation of the natural history of HPV has preventive as well as etiologic importance. [J Natl Cancer Inst 85:958-964, 1993] The well-established association between sexual activity and the development of .cervical neoplasia strongly impli- cates a sexually transmissible etiologic agent (1,2). Molecu- lar studies have provided strong evidence that human papillomavirus (HPV) may be this agent (3), but the epidemiologic evidence has been weaker (4,5). HPV DNA is identified much more frequently in women with cervical neoplasia than in women with normal cervical cytologic diagnoses. Moreover, statistical adjustment for HPV infec- tion has not explained the elevated risk of developing cervical neoplasia in women with multiple sex partners, suggesting that other venereally transmitted agents play an etiologic role (6-9). In addition, the estimated proportion of cervical neoplasia attributable to HPV infection in previous studies has been too low for one to conclude that HPV infection causes most cervical neoplasia. Recently, improved HPV testing methods revealed for the first time a strong link between sexual activity history and cervical HPV infection (70). This finding prompted our large case-control study of cervical intraepithelial neoplasia (CIN) and HPV infection, which evaluates whether sexual behavior and the other established risk factors for cervical neoplasia influence risk primarily via HPV infection. *See Notes section following References.