This competing continuation grant is the second and last request for renewal of CA70269, the original funding for an epidemiologic study of the natural history of human papillomavirus (HPV) infection and cervical neoplasia in a low-income female population in Sao Paulo, Brazil. In collaboration with Brazilian colleagues, three of the authors began the study in 1993 in an attempt to understand attributes of the natural history of HPV that could be instrumental in designing strategies for preventing cervical cancer. Considering the public health and economic importance of cervical cancer and the widespread interest in HPV vaccines and in using HPV in cancer screening there is a need for long-ranging multidisciplinary studies of the natural history of HPV. The study accrued 2529 female subjects through March 1997. Subjects have been followed up in scheduled returns every 4 months in the first year, and twice yearly thereafter for a total of 5 years. Participants undergo a questionnaire-based interview have a cervical specimen taken for Pap cytology and HPV testing, and a blood sample drawn for HPV antibody serology. Follow-up will have been completed at the time current funding for the cohort study finishes in August 2002. The study's original objectives (1996-99 funding period) were: (1) to study the prevalence and incidence of persistent HPV infection in asymptomatic women; (2) to verify the hypothesis that persistent HPV infection increases risk of cervical lesions; (3) to search for determinants of persistent cervical HPV infection; (4) to search for molecular variants of HPV that may lead to an increased risk of cervical lesions; (5) to verify the hypothesis that viral burden in the cervix may be correlated with persistent infections and with lesion risk; and (6) to study the antibody response to HPV as a predictor of persistent HPV infection and of lesion risk. In the last successful continuation (1999-02 funding period) these objectives were expanded to include: (7) the search for specific HLA haplotypes associated with HPV persistence and lesion severity, and (8) to test the hypothesis that p53 gene polymorphism may influence resistance against viral persistence and to lesion development. This competing continuation is to conduct in-depth statistical analyses of the database accrued during the study and to add a new objective: (9) to study the role of insulin growth factors in mediating risk of persistent HPV infection and cervical lesions.
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