The Epidemiological Study On Human Papillomavirus And The Effect Of Risk Factors Of Cervical Cancer In HPV Screening In Zhejiang Province

Human papillomavirus (HPV) has been shown to be the etiologic agent of anogenital cancers, especially cervical cancer, and a fraction of oropharyngeal carcinomas. More than 100 HPV genotypes have been molecularly characterized. Based on epidemiologic classification associated with cervical cancer, HPV types are categorized as established high-risk types (HR) (eg., HPV-16,-18), probably HR types (eg., HPV-26,-53) and established low-risk (LR) types (eg., HPV-6, -11). Current available prophylactic HPV vaccines, which are based on the epidemiologic data in European and American areas, focus on HPV-16 and -18. Since limited cross-protection would be offered for other types, heterogeneity in HPV type-specific distribution from different populations should be taken into account when predicting the effect of current prophylactic vaccines and forming the basic for the second-generation vaccines targeted to specific regions. To the best of our knowledge, no epidemiologic data on HPV genotypes in general female population were reported from Zhejiang Province.Cervical HPV infections are extremely common and most infections are cleared spontaneously. However, persistent infection, especially HR-HPV persistence, substantially increases the risk for precancerous cervical lesions and invasive cervical cancer (ICC). The factors associated with persistent vs transient HPV infection are poorly understood. Considering the differences in host and environmental factors, natural history of HPV infection may vary among different populations. Previous studies have contributed a lot to the natural history of HPV infection, while no reports were from general female population in mainland China.Cervical cancer, which is closed related with HPV infection, is the second most common malignancy among women worldwide. Primary screening by cervical cytology has substantially reduced the incidence of ICC in developed countries with organized programs over the past 50 years. However, effective cytology-based screening relies on intensive infrastructure and well-trained personnel to ensure high quality, which may be unattainable in most of developing countries. HPV infection is a prerequisite of ICC, thus HPV DNA testing for HR-HPV types has been proposed for cervical cancer screening, either alone or in combination with cytology. Compared with cytology, HR-HPV testing is more objective and sensitive, but less specific for the detection of high-grade cervical intraepithelial neoplasia (CIN) in primary screening. Adding "cytological triage" to HR-HPV testing represents an improvement, however, such a primary screening strategy with two screening systems might be costly. What is more, it has been widely recommended that management for women with positive HR-HPV but normal cytology is repeated HR-HPV testing and cytology after one year. However, the long-term follow-up may produce psychological stress and anxiety or cause loss of patients. Pervious studies had contributed a lot to the risk factors of cervical cancer. However, to the best of our knowledge, up to data, there are no reports on the application of risk factors in the triage management of HR-HPV positive population.In this study, we intended to be conscious of cervical HPV prevalence, HPV persistence and predictors concerned in asymptomatic general female population in Zhejiang Province with population-based study. These would be valuable in the implement of the first-generation vaccines, development of the second-generation vaccines and the estimation of HPV persistence likelihood in this area. With population-based primary screening, we investigated whether risk factors could be used in the triage management of HR-HPV positive population for detecting CINⅡor worse (CINⅡ+).PART I Prevalence and risk profile of HPV infection in asymptomatic general female population in Zhejiang ProvinceObjectives:To be conscious of cervical HPV prevalence, as well as predictors concerned, in asymptomatic general female population in Zhejiang Province.Methods:A structured questionnaire was used to collect epidemiologic data and the cervical sampler was used to collect exfoliated cervical cells. HPV genotyping was performed with HPV GenoArray Test Kit, complementary with polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). Statistical analysis was performed using X2 test or Fisher's exact test, and unconditional logistic regression.Results:1. Totally 4987 cervical samples from five different areas in Zhejiang Province were detected. The overall HPV prevalence was 13.3%. Established HR-HPV prevalence was 10.2%. HPV-52 was the most common type (3.1%), followed by HPV-16 (2.5%), HPV-58 (2.1%), HPV-68 (1.0%) and HPV-81 (0.9%). HPV-16 and/or -18 were present in 3.1%of the detected samples, while 174 specimens (3.5%) were positive for any of HPV-6,-11,-16 and-18.2. Bimodal age distribution in HR-HPV prevalence, including established HR and probably HR-HPV, was observed, with the second peak in perimenopausal women. Prevalence of HPV vaccine types was consistently low across age groups.3. Multivariate unconditional logistic models revealed that partner's lifetime number of partners was the only common determinant of overall, established HR, established LR, single-type and multiple-type HPV infection in our population.Conclusions:1. Relatively low prevalence of vaccine types and relatively high prevalence of HPV-52 and -58 were observed in asymptomatic general female population in Zhejiang Province, indicating that the second-generation prophylactic vaccines including HPV-52 and -58 may offer higher protection for women in this area.2. There were two peaks of HPV infection in asymptomatic general female population in Zhejiang Province. The latter peak was probably associated with increased viral persistence or reactivation of latent HPV.PART II Type-specific HPV persistence and its predictors in asymptomatic general female population in Zhejiang provinceObjectives:To be conscious of the type-specific HPV persistence and associated predictors in asymptomatic general female population in Zhejiang province.Methods:Persistence was evaluated in 548 women who were positive at enrollment and returned after 6-14 months. Liquid-based cytology screening was also encouraged for women returned. Statistical analysis was performed using x2 test or Fisher's exact test, analysis of variance and unconditional logistic regression.Results:1. Overall persistence was 49.1%(269/548), while established HR-HPV persistence was 54.5%(218/400).2. The types with the highest persistence were HPV-52,-58,-56, and-16, most of which belonged to alpha-9 species.3. Total 252 women refused cytology screening and no differences were found among overall follow-up women, women accepting cytology screening and women refusing cytology screening with regard to HPV persistence and other variables concerned. No differences were found for persistence of most types between women with normal cytology and abnormal cytology, except for HPV-58 (P=0.004) and -81 (P=0.036) among women 35 years and older.4. Established HR-HPV persistence increased with age, low income and early sexual debut.Conclusions:1. HR-HPV persistence increased with age, indicating that HR-HPV positivity has more important clinical meaning for older women than for younger women. Thus, intensive screening is recommended for older women with HR-HPV infection.2. Women with non-alpha-9 HPV positivity and no risk factors had relatively lower persistent chance. PARTⅢApplication of risk factors of cervical cancer in triage management of HR-HPV positive populationObjectives:To evaluate the effect of risk factors of cervical cancer in triage management of HR-HPV positive population in primary cervical cancer screening.Methods:Risk factors of ICC were obtained with hospital-based case-control study and included as potential triage factors. In population-based cervical cancer screening, potential triage factors associated with CINⅡ+were selected as triage factors. Performance of HR-HPV testing with triage factors was evaluated for detecting CINⅡ+. Statistical analysis was performed usingχ2 test or Fisher's exact test, and unconditional logistic regression.Results:1. Total 1045 women were enrolled in case-control study, including 427 cases and 618 controls. Multivariate analysis revealed that single status, smoking, passive smoking, low income, early sexual debut, frequent sexual activities and multiple lifetime number sexual partners were independent risk factors for ICC.2. Lifetime number of sexual partners was selected as a triage factor. With triage factor, the specificity of HR-HPV testing increased significantly, both in women with normal cytology (P= 0.000) and abnormal cytology (P= 0.030). While stratified with age, no significant differences were observed for women younger than 30 years, whereas the specificity and accuracy of HR-HPV testing increased significantly with triage factor (P=0.000 and P=0.000, respectively) among women aged 30 years or older.Conclusions:1.Passive smoking was an independent risk factor for cervical cancer, thus control of smoking in public place was worth encouraging.2.As single status was an independent risk factor for cervical cancer, cervical cancer screening should include unmarried women in case they have sexual activities.3.Triage with lifetime number of sexual partners could increase the specificity of HR-HPV testing in primary cervical cancer screening.