Host and Viral Factors in Relation to Outcome of HPV Latent Infection---A Long-Term Follow-Up Study

Specific Aims: (1) to continue long-term follow up in a population-based cohort of women with latent HPV infection; (2) to incorporate the other viral (HPV genotype, integration, and viral load) and demographic factors into the multivariate analysis of significant variables in relation to outcome (viral clearance or develop lesions equal to or severer than cervical intraepithelial neoplasia grade 2 [＞=CIN2]); (3) to study the host factors by screening genetic markers covering the TNF-α promoter, IL10, and interferon-γpromoter single nucleotide polymorphism (SNP) for involvement in the pathogenesis of cervical epithelial neoplasms. Infection by HPV is a major event in the development of intraepithelial lesions and subsequent cervical carcinoma. Moreover, the prevalence of genital-tract HPV infections has been reported to range from 1.4-25.6% in general population. Identifying latent cervical HPV infection might improve the detection of cervical neoplasia and be a first step toward blocking the natural progression of cervical cancer. Persistence of high-risk HPV infection is more likely to progress. Several risk factors such as age, menopausal state, parity, multiple sexual partners, high-risk male consort, oral pills use, hormone replacement therapy, smoking, and higher viral load have been reported associated with HPV persistence or developing cervical neoplasia. In our previous study, a total of 10,014 women from Taoyuan have been accrued for Pap smear and HPV DNA testing as primary cervical screening. Every participant had a Pap smear and a second swab for HPV Blot testing. 970 women had normal cytology, but positive HPV DNA (Group II). All these patients were called for a colposcopic examination and directed biopsy. 626 women were eligible for follow-up study: Group IIa1 (normal colposcopy) and 106 Group IIa2 (abnormal colposcopy but negative biopsy). 526 women had signed informed consent and been accrued in our previous study (NSC95-2314-B-182-058-MY2) and 412 of them attended at least one follow-up. According to old literature ref.8, 11.6% in 2 years (62 events) of subjects would develop ＞=CIN2 lesions, which number of events will be sufficient for analysis of primary end point. However, the 3-year clearance rates of HPV were inversely associated with multiple types, HPV-52 or -53, older age, and menopausal status. Only 15 cases (3.6%)of ＞=CIN2 were identified. Owing to scanty events, no host or viral factor was significant predictor of progression to ＞=CIN2. will be asked to continue another 3 years follow-up. Those Group IIb patients will be contacted again and presumed 50 might consent to join this study. Additional 5000 women primary screening will be done in the first year to collect approximated 350 subjects to make a total of 800 participants. In the first year, we will perform primary screening 5000 women (2000 participants funded by this project and the remaining 3000 by CMRP) and obtained re-consent to extend follow up from IIa1 and IIa2 as well as re-inviting Group IIb to join. In the second year, we will continue follow up these 800 subjects and optimizing the methodology of HPV integration, viral load of rare type and TNF-α promoter, IL-10 and interferon-γpromoter SNP analysis. In the third year, keep following up participants and obtain national registry data for outcome analysis. This project will provide useful information for women with HPV latent infection found by incorporating HPV testing and Pap smear in the primary screening, to help those women to cope with the anxiety and also facilitate elucidating an appropriate management strategy. It will significantly impact the future role of clinical HPV testing in Taiwan as well as in the world.

Project ID:PC9801-2146
External Project ID:NSC97-2314-B182-013-MY3